Aminophosphonic acid derivatives, addition salts thereof and sip receptor modulators

ABSTRACT

Aminophosphonic acid derivatives (e.g., 2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentylphosphonate monoester) are represented by the following general formula (1):  
                 
and act as effective S1P receptor modulators while posing less side effects.

TECHNICAL FIELD

The present invention relates to aminophosphonic acid derivatives, saltsand hydrates thereof that are useful as modulators ofsphingosine-1-phosphate (S1P) receptor.

BACKGROUND ART

Patent Article 1 WO pamphlet 0198301 Patent Article 2 WO pamphlet03020313 Patent Article 3 WO pamphlet 02092068 Patent Article 4 WOpamphlet 0218395 Patent Article 5 WO pamphlet 02076995 Patent Article 6Japanese Patent Laid-Open

Publication No. Hei 2003-137894 Patent Article 7 WO Pamphlet 03040097Patent Article 8 WO Pamphlet 02064616 Patent Article 9 WO Pamphlet02062389 Patent Article 10 WO Pamphlet 03051876 Patent Article 11 WOPamphlet 03061567 Patent Article 12 WO Pamphlet 03062248 Patent Article13 WO Pamphlet 03062252 Patent Article 14 WO Pamphlet 03073986

Non-Patent Article 1 Y. Takuma et al., Mol. Cell. Endocrinol., 177,3(2001)

Non-Patent Article 2 Y. Igarashi, Ann, N.Y. Acad. Sci., 845, 19(1998)

Non-Patent Article 3 H. Okazaki et al., Biochem. Biophs. Res. Commun.,190, 1104(1993)

Non-Patent Article 4 S. Mandala et al., Science, 296, 346(2002)

Non-Patent Article 5 V. Brinkmann et al., J. Biol. Chem., 277,21453(2002)

Sphingosine-1-phosphate (referred to simply as S1P, hereinafter), whichwas previously considered a mere intermediate product in the metabolismof sphingosine, has proven to have an ability to facilitate cell growthand regulate cell motility. Studies have now shown that S1P, apreviously unknown lipid mediator, is involved in a wide range ofphysiological actions, including apoptisis, modification of cellmorphology and vascular contraction (Non-Patent Article 1 and Non-PatentArticle 2). The lipid acts both as an intracellular second messenger andas an intercellular mediator; its role as an intercellular mediator hasbeen particularly intensively studied. S1P induces signal transductionvia a family of cell membrane G-protein-coupled receptors designated asEdg (which stands for Endothelial Differential Gene) (Non-Patent Article1 and Non-Patent Article 3). Currently known subtypes of S1P receptorsare Edg-1, Edg-3, Edg-5, Edg-6 and Edg-8, which are also referred to asS1P₁, S1P₃, S1P₂, S1P₄ and S1P₅, respectively.

Many studies of these S1P receptors suggest that S1P receptormodulators, which bind to these receptors and act as agonists orantagonists of S1P receptors, are effective against a broad spectrum ofdiseases. For example, compounds that act on Edg-5 have been showneffective against arteriosclerosis, renal fibrosis, pulmonary fibrosisand hepatic fibrosis (Patent Article 1). Compounds that act on Edg-1,Edg-3 or Edg-5 have been shown to be effective therapeutic orprophylactic agents against various respiratory diseases, includingchronic bronchial asthma, diffuse pulmonary hamartoangiomyomatosis,adult respiratory distress syndrome (ARDS), chronic obstructivepulmonary disease (COPD), interstitial pneumonia, idiopathicinterstitial pneumonia, lung cancer and hypersensitivity pneumonitis(Patent Article 2). In addition, compounds that act as Edg-1 agonistshave been shown to be effective therapeutic or prophylactic agents forperipheral vascular diseases, such as arteriosclerosis obliterans,thromboangiitis obliterans, Buerger's disease and diabetic neuropathy,septicemia, angiitis, nephritis, pneumonia, cerebral infarction,myocardial infarction, edema, arteriosclerosis, varicose veins, such aspiles, anal fissure and anal fistula, dissecting arterial aneurysm,stenocardia, DIC, pleuritis, congestive heart failure, multiple organfailure, bed sore, burn, ulcerative colitis, Crohn's disease, hearttransplantation, kidney transplantation, skin transplantation, livertransplantation, bone marrow transplantation, osteoporosis, chronichepatitis, hepatic cirrhosis, chronic renal failure andglomerulosclerosis (Patent Article 3). Furthermore, compounds that actas agonists of S1P receptors have been shown to modulate the migrationof leukocytes (Non-Patent Article 4 and Non-Patent Article 5). Moreover,the derivatives mentioned in the aforementioned Non-Patent Articles havebeen shown effective not only against various organ transplants andGVHD, but also against autoimmune diseases, such as rheumatoidarthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto'sdisease, multiple sclerosis, myasthenia gravis, type I and type IIdiabetes and Crohn's disease, allergic diseases, such as atopicdermatitis, allergic rhinitis, allergic conjunctivitis, allergic contactdermatitis, and inflammatory diseases, such as inflammatory boweldisease and ulcerative colitis (Patent Article 4 and Patent Article 5).Phosphoric acid derivatives similar to what are described in PatentArticles 4 and 5 and act as antagonists of S1P receptors are describedin Patent Article 6. Other S1P receptor modulators are disclosed inPatent Articles 7, 8, 9 and 10.

In the course of the studies to develop compounds that have an abilityto modulate S1P receptors, which are involved in the onset of variousdisorders, the present inventors have drawn the attention toaminophosphonic acid derivatives having different structures frompreviously known compounds and have made an effort in searching fornovel modulators of S1P receptors. Quite recently, S1P receptor agonistshaving an amino group along with a phosphonic acid unit were disclosedin Patent Articles 11, 12 and 13. Each of these compounds has astructure in which the amino group is integrated in their linkingbackbone. This structure differs from the structure of the compounds ofthe present invention, which essentially has the form ofβ-aminophosphonic acid or γ-aminophosphonic acid in which an amino groupexists on the linking backbone. Patent Article 14 describes similarcompounds but the compounds of the present invention are not included.

DISCLOSURE OF THE INVENTION

It is thus an objective of the present invention to provide anaminophophonic acid derivative that can effectively modulate S1Preceptors with less side effects.

The present inventors have conducted extensive studies to find compoundsthat have an ability to modulate S1P receptors and are highly safe. As aresult, the inventors have found that certain aminophosphonic acidderivatives with a diarylsulfide or diarylether group that have adifferent structure from any of previously known S1P receptor modulatorsact as potent modulators of S1P receptors. It is this finding that ledto the present invention.

Accordingly, the present invention provides an S1P receptor modulatorcontaining as an active ingredient at least one of aminophosphonic acidderivatives represented by the following general formula (1):

[wherein R₁ is a hydrogen atom, a halogen atom, a halogenated orunhalogenated lower alkyl group having 1 to 4 carbon atoms, a hydroxygroup, a phenyl group, an aralkyl group, a lower alkoxy group having 1to 4 carbon atoms, a trifluoromethyloxy group, a substituted orunsubstituted phenoxy group, a cyclohexylmethyloxy group, a substitutedor unsubstituted aralkyloxy group, a pyridylmethyloxy group, acinnamyloxy group, a naphthylmethyloxy group, a phenoxymethyl group, ahydroxymethyl group, a hydroxyethyl group, a lower alkylthio grouphaving 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, abenzylthio group, an acetyl group, a nitro group or a cyano group; R₂ isa hydrogen atom, a halogen atom, a halogenated or unhalogenated loweralkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to4 carbon atoms, an aralkyl group or an aralkyloxy group; R₃ is ahydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkylgroup having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4carbon atoms, a hydroxy group, a benzyloxy group, a phenyl group, alower alkoxymethyl group having 1 to 4 carbon atoms or a lower alkylthiogroup having 1 to 4 carbon atoms; R₄ is a hydrogen atom, a halogen atom,a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxymethylgroup having 1 to 4 carbon atoms, a lower alkylthiomethyl group having 1to 4 carbon atoms, a hydroxymethyl group, a phenyl group or an aralkylgroup; R₅ is a hydrogen atom or a lower alkyl group having 1 to 4 carbonatoms; X is O, S, SO or SO₂; Y is —CH₂O—, —CH₂—, —CH═CH—, —CH═CF—,—CH₂CH₂—, —CH₂CFH—, —CH₂CF₂— or —CH(OH)CF₂—; and n is an integer from 1to 4], and an optical isomer, and a pharmaceutically acceptable salt anda hydrate thereof.

More specifically,

(I) the present invention provides: an aminophosphonic acid derivativerepresented by the following general formula (1):

[wherein R₁, R₂, R₃, R₄, R₅, Y and n are as defined above], and anoptical isomer, and a pharmaceutically acceptable salt and a hydratethereof;

(II) 2-aminophosphonic acid monoester derivative represented by thefollowing general formula (1a):

[wherein R₃, R₄, X and n are as defined above], and the optical isomer,and the pharmaceutically acceptable salt and the hydrate thereof;

(III) 2-aminophosphonic acid monoester derivative represented by thegeneral formula (1a) and the optical isomer, and the pharmaceuticallyacceptable salt and the hydrate thereof;

(IV) 3-aminophosphonic acid derivative represented by the followinggeneral formula (1b):

[wherein z is CH₂—, —CH═CH—, —CH═CF—, —CH₂CH₂—, —CH₂CHF—, —CH₂CF₂— or—CH(OH)CF₂—; and R₃, R₄, X and n are as defined above], and the opticalisomer, and the pharmaceutically acceptable salt and the hydratethereof;

(V) 3-aminophosphonic acid derivative represented by the general formula(1b), and the optical isomer, and the pharmaceutically acceptable saltand the hydrate thereof, wherein R₃ is a chlorine atom; and

(VI) An S1P receptor modulator containing as an active ingredient atleast one of the compounds of (I) to (V) above.

The compounds of the general formulae (1), (1a) and (1b) are novelcompounds.

Among preferred compounds of the present invention are aminophosphonicacid ester derivatives according to claim 1, including 1)2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentylphosphonicacid monoester, 2)2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutylphosphonicacid monoester, 3)2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylpentylphosphonicacid monoester, 4)2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylbutylphosphonicacid monoester, 5)3-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylpentylphosphonicacid and 6)3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylhexylphosphonicacid, and pharmaceutically acceptable salts and hydrates thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Pharmaceutically acceptable alkaline salts of the compounds representedby the general formula (1) according to the present invention includesodium salts, potassium salts, magnesium salts, calcium salts andaluminum salts. Acid salts of the compounds represented by the generalformula (1) include hydrochlorides, hydrobromides, acetates,trifluoroacetates, methanesulfonates, citrates and tartarates.

The halogen atom in the general formula (1) may be fluorine, chlorine,bromine or iodine. The lower alkyl group as in the “lower alkyl grouphaving 1 to 4 carbon atoms,” the “lower alkoxy group having 1 to 4carbon atoms,” the “lower alkylthio group having 1 to 4 carbon atoms,”the “lower alkyl group sulfinyl having 1 to 4 carbon atoms,” the “loweralkyl sulfonyl group having 1 to 4 carbon atoms” or the “loweralkoxymethyl group having 1 to 4 carbon atoms” in the general formula(1) is a straight-chained or branched hydrocarbon having 1 to 4 carbonatoms, including methyl, ethyl, propyl, isopropyl, butyl and t-butyl.The “substituted or unsubstituted phenoxy group” or “substituted orunsubstituted aralkyl group” in the general formula (1) is a phenoxy oraralkyl group that has at some position on its benzene ring a halogenatom, such as a fluorine atom, a chlorine atom, a bromine atom and aniodine atom, a trifluromethyl group, a lower alkyl group having 1 to 4carbon atoms or a lower alkoxy group having 1 to 4 carbon atoms. The“aralkyl group” as in “aralkyl group”or “aralkyloxy group” in thegeneral formula (1) may be a benzyl group, a diphenylmethyl group, aphenethyl group or a phenylpropyl group.

Of the compounds represented by the general formula (1) according to thepresent invention, those in which Y is —CH₂O— and R5 is a lower alkylgroup having 1 to 4 carbon atoms, which are represented by the followinggeneral formula (1c):

(wherein R₆ is a lower alkyl group having 1 to 4 carbon atoms; and R₁,R₂, R₃, R₄, X and n are as defined above) can be produced through thefollowing pathway:

In the synthetic pathway 1, the compound represented by the followinggeneral formula (3):

(wherein R₇ is a lower alkyl group having 1 to 4 carbon atoms; and R₁,R₂, R₃, R₄, X and n are as defined above) can be obtained by reacting acompound represented by the following general formula (2):

(wherein A is a chlorine atom, a bromine atom or an iodine atom; and R₁,R₂, R₃, X and n are as defined above) with a compound represented by thefollowing general formula (8):

(wherein R₄ and R₇ are as defined above) in the presence of a base (StepA).

This reaction may use methanol, ethanol, 1,4-dioxane, dimethylsulfoxide(DMSO), N,N-dimethylformamide (DMF) or tetrahydrofurane (THF) as areaction solvent and may be carried out at a reaction temperature of 0°C. to reflux temperature, preferably 80° C. to 100° C., and in thepresence of an inorganic base such as sodium hydride, potassium hydride,sodium alkoxide, potassium alkoxide, potassium carbonate and sodiumcarbonate.

In the synthetic pathway 1, the compound represented by the followinggeneral formula (4):

(wherein R₁, R₂, R₃, R₄, R₇, X and n are as defined above) can beobtained by hydrolysis of the compound of the general formula (3) (StepB).

This reaction may use methanol, ethanol, 1,4-dioxane, DMF or DMSO as areaction solvent and may be carried out at a reaction temperature of 0°C. to reflux temperature and in the presence of a base, such as aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.Preferably, the compound of the general formula (3) is reacted withpotassium hydroxide in an ethanol solvent at 50° C.

In the synthetic pathway 1, the compound represented by the followinggeneral formula (5):

(wherein R₈ is a lower alkyl group having 1 to 4 carbon atoms; and R₁,R₂, R₃, R₄, R₇, X and n are as defined above) can be obtained byallowing the compound of the general formula (4) to undergo Curtisrearrangement (Step C).

This reaction can be carried out by using common techniques forconverting a carboxyl group into a carbamate. One such techniqueinvolves the use of ethyl chlorocarbonate and NaN₃. Another preferredtechnique involves heating diphenylphosphoryl azide (DPPA) in a benzeneor toluene solvent in the presence of a base such as triethylamine whilestirring the mixture, followed by addition of a lower alcohol such asmethanol, ethanol, propanol, isopropanol, butanol and t-butanol and thenfurther heating while stirring the mixture. Alternatively, the reactionmay use only a lower alcohol as a reaction solvent and is carried out byheating and stirring the mixture and, preferably, by heat-refluxing themixture.

In the synthetic pathway 1, the compound represented by the followinggeneral formula (6):

(wherein R₁, R₂, R₃, R₄, R₈, X and n are as defined above) can beobtained by the reduction of the compound of the general formula (5)(Step D).

This reaction may use an alkylborane derivative such as borane (BH₃) and9-borabicyclo[3.3.1]nonane(9-BBN) and a metal hydride complex such asdiisobutylaluminum hydride ((iBu)₂AlH), sodium borohydride (NaBH₄) andlithium aluminum hydride (LiAlH₄), preferably lithium borohydride(LiBH₄), and uses THF, 1,4-dioxane, ethanol or methanol as a reactionsolvent. The reaction may typically be carried out at a reactiontemperature of 0° C. to reflux temperature, preferably at roomtemperature.

In the synthetic pathway 1, the compound represented by the followinggeneral formula (7):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reacting the compound of the general formula (6) with acompound represented by the following general formula (9):P(OR₆)₃   (9)(wherein R₆ is as described above) (Step E).

This reaction may be carried out without any solvent or by usingmethylene chloride, chloroform, acetonitrile, ethyl acetate, THF orether as a dilution solvent and may be carried out at a reactiontemperature of 0° C. to room temperature and in the presence of carbontetrabromide and pyridine.

In the synthetic pathway 1, the compound of the general formula (1c) canbe obtained by acidolysis or hydrolysis of the compound of the generalformula (7) (Step F).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature. Alternatively, the reaction may use methanol, ethanol,1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may be carriedout at a reaction temperature of 0° C. to reflux temperature, preferably80° C. to 100° C., and in the presence of a base such as an aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.

Of the compounds represented by the general formula (1), those in whichR₄ is a hydrogen atom or a hydroxymethyl group, R₅ is a lower alkylgroup having 1 to 4 carbon atoms and Y is — CH₂O— and which arerepresented by the following general formula (1d):

(wherein R₉ is a hydrogen atom or a hydroxymethyl group; and R₁, R₂, R₃,R₆, X and n are as defined above) can be produced through the followingpathway:

In the synthetic pathway 2, the compound represented by the followinggeneral formula (10):

(wherein Boc is t-butoxycarbonyl group; and R₁, R₂, R₃, R₇, X and n areas defined above) can be obtained by reacting the compound of thegeneral formula (2) with a compound represented by the following generalformula (13):

(wherein R₇ and Boc are as defined above) in the presence of a base(Step G).

This reaction may use methanol, ethanol, 1,4-dioxane, DMSO, DMF or THFas a reaction solvent and may be carried out at a reaction temperatureof 0° C. to reflux temperature, preferably 80° C. to 100° C., and in thepresence of an inorganic base such as sodium hydride, potassium hydride,sodium alkoxide, potassium alkoxide, potassium carbonate and sodiumcarbonate.

In the synthetic pathway 2, the compound represented by the followinggeneral formula (11):

(wherein R₁, R₂, R₃, R₉, X, Boc and n are as defined above) can beobtained by reduction of the compound of the general formula (10) (StepH).

This reaction may use an alkylborane derivative such as BH₃ and 9-BBNand a metal hydride complex such as (iBu)₂AlH, NaBH₄ and LiAlH₄,preferably LiBH₄, and uses THF, 1,4-dioxane, ethanol or methanol as areaction solvent. The reaction may be carried out at a reactiontemperature of 0° C. to reflux temperature, preferably at roomtemperature.

In the synthetic pathway 2, the compound represented by the followinggeneral formula (12):

(wherein R₁, R₂, R₃, R₆, R₉, X, Boc and n are as defined above) can beobtained by reacting the compound of the general formula (11) with acompound represented by the following general formula (9):P(OR₆)₃   (9)(wherein R₆ is as described above) (Step I).

This reaction may be carried out without any solvent or by usingmethylene chloride, chloroform, acetonitrile, ethyl acetate, THF orether as a solvent and may be carried out at a reaction temperature of0° C. to room temperature and in the presence of carbon tetrabromide andpyridine.

In the synthetic pathway 2, the compound of the general formula (1d) canbe obtained by acidolysis of the compound of the general formula (12)(Step J).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature.

Of the compounds represented by the general formula (1), those in whichY is —CH═CH— or —CH₂—CH₂— and R₅ is a lower alkyl group, which arerepresented by the following general formula (1e):

(wherein W is —CH═CH— or —CH₂—CH₂—; and R₁, R₂, R₃, R₄, R₆, X and n areas defined above) can be produced through the following syntheticpathway 3:

In the synthetic pathway 3, the compound represented by the followinggeneral formula (14):

(wherein R₁, R₂, R₃, R₄, R₈, X and n are as defined above) can beobtained by oxidation of the compound of the general formula (6) (StepK).

This reaction may be carried out using a common technique for oxidizingalcohol into aldehyde. Among agents used in these techniques arechromium oxide/pyridine complexes, such as pyridinium chlorochromate andpyridinium dichromate, and metal oxidizing agents, such as chromiumoxide, silver carbonate and manganese dioxide. DMSO oxidation using DMSOactivating agents, such as oxalyl chloride, anhydrous trifluoroaceticacid, anhydrous acetic acid, DCC and sulfur trioxide/pyridine complex,may also be employed.

In the synthetic pathway 3, the compound represented by the followinggeneral formula (15):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reacting the compound of the general formula (14) with acompound represented by the following general formula (19):

(wherein R₆ are as defined above) in the presence of a base (Step L).

This reaction may use THF, ether or 1,4-dioxane as a reaction solventand can be carried out at a reaction temperature of −78° C. to roomtemperature and in the presence of sodium hydride, potassium hydride,sodium alkoxide or potassium alkoxide, preferably n-butyllithium.

In the synthetic pathway 3, the compound represented by the followinggeneral formula (16):

(wherein R₁, R₂, R₃, R₄, R₆, X and n are as defined above) can beobtained by acidolysis or hydrolysis of the compound of the generalformula (15) (Step M).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and is preferably carried out at a reaction temperature of 0° C.to room temperature. Alternatively, the reaction may use methanol,ethanol, 1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may becarried out at a reaction temperature of 0° C. to reflux temperature,preferably 80° C. to 100° C., and in the presence of a base such as anaqueous solution of sodium hydroxide, potassium hydroxide or lithiumhydroxide.

In the synthetic pathway 3, the compound represented by the followinggeneral formula (17):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reduction of the compound of the general formula (15) (StepN).

This reaction can be carried out in the presence of a reductioncatalyst, such as palladium carbon, platinum carbon, platinum oxide,rhodium carbon and ruthenium carbon, and in such a solvent as ethanol,methanol, THF, DMF and ethyl acetate and is carried out at roomtemperature under a hydrogen pressure of atmospheric or higher pressure.

In the synthetic pathway 3, the compound represented by the followinggeneral formula (18):

(wherein R₁, R₂, R₃, R₄, R₆, X and n are as defined above) can beobtained by acidolysis or hydrolysis of the compound of the generalformula (17) (Step O).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature. Alternatively, the reaction may use methanol, ethanol,1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may be carriedout at a reaction temperature of 0° C. to reflux temperature, preferably80° C. to 100° C., and in the presence of a base such as an aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.

The compound of the general formula (18) can also be obtained byreduction of the compound of the general formula (16) (Step P). In sucha case, the reaction may be carried out in the presence of a reductioncatalyst, such as palladium carbon, platinum carbon, platinum oxide,rhodium carbon and ruthenium carbon, and in such a solvent as ethanol,methanol, THF, DMF and ethyl acetate and may be carried out under ahydrogen pressure of atmospheric or higher pressure at room temperature.

Of the compounds represented by the general formula (1), those in whichY is —CH═CF— or —CH₂CHF— and R₅ is a lower alkyl group having 1 to 4carbon atoms, which are represented by the following general formula(1f):

(wherein Q is —CH═CF— or —CH₂CHF—; and R₁, R₂, R₃, R₄, R₆, X and n areas defined above) can be produced through the following syntheticpathway 4:

In the synthetic pathway 4, the compound represented by the followinggeneral formula (20):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reacting the compound of the general formula (14) with thecompound represented by the following general formula (24):FBr₂CPO(OR₆)₂   (24)(wherein R₆ is as defined above) in the presence ofchlorotrimethylsilane (Step Q).

This reaction may use n-butyllithium or lithium diisopropylamide as abase and 1,4-dioxane, ether or, preferably, THF as a solvent and may becarried out at −78° C. to 0° C.

In the synthetic pathway 4, the compound represented by the followinggeneral formula (21):

(wherein R₁, R₂, R₃, R₄, R₆, X and n are as defined above) can beobtained by acidolysis or hydrolysis of the compound of the generalformula (20) (Step R).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature. Alternatively, the reaction may use methanol, ethanol,1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may be carriedout at a reaction temperature of 0° C. to reflux temperature, preferably80° C. to 100° C., and in the presence of a base such as an aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.

In the synthetic pathway 4, the compound represented by the followinggeneral formula (22):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reduction of the compound of the general formula (20) (StepS).

This reaction can be carried out in the presence of a reductioncatalyst, such as palladium carbon, platinum carbon, platinum oxide,rhodium carbon and ruthenium carbon, and in such a solvent as ethanol,methanol, THF, DMF and ethyl acetate and may be carried out at roomtemperature under a hydrogen pressure of atmospheric or higher pressure.

In the synthetic pathway 4, the compound represented by the followinggeneral formula (23):

(wherein R₁, R₂, R₃, R₄, R₆, X and n are as defined above) can beobtained by reduction of the-compound of the general formula (21) (StepT) or acidolysis or hydrolysis of the compound of the general formula(22) (Step U).

This reduction process can be carried out in the presence of a reductioncatalyst, such as palladium carbon, platinum carbon, platinum oxide,rhodium carbon and ruthenium carbon, and in such a solvent as ethanol,methanol, THF, DMF and ethyl acetate and may be carried out at roomtemperature under a hydrogen pressure of atmospheric or higher pressure.The acidolysis or hydrolysis process may be carried out in an inorganicacid or organic acid such as acetic acid, hydrochloric acid, hydrobromicacid, methanesulfonic acid and trifluoroacetic acid or in a mixture withan organic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature. Alternatively, the reaction may use methanol, ethanol,1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may be carriedout at a reaction temperature of 0° C. to reflux temperature, preferably80° C. to 100° C., and in the presence of a base such as an aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.

Of the compounds represented by the general formula (1), those in whichR₅ is a lower alkyl group having 1 to 4 carbon atoms and Y is —CH₂—,—CH₂CH₂—, —CH₂CHF— or —CH₂CF₂—, which are represented by the followinggeneral formula (1g):

(wherein T is —CH₂—, —CH₂CH₂—, —CH₂CHF— or —CH₂CF₂—; and R₁, R₂, R₃, R₄,R₆, X and n are as defined above) can be produced through the followingsynthetic pathway 5:

In the synthetic pathway 5, the compound represented by the followinggeneral formula (25):

(wherein U is an iodine atom, a bromine atom, a methanesulfonyloxy groupor a trifluoromethanesulfonyloxy group; and R₁, R₂, R₃, R₄, R₈, X and nare as defined above) can be produced from the compound of the generalformula (6) (Step V).

For the introduction of methanesulfonyloxy group ortrifluoromethanesulfonyloxy group, an organic solvent such as methylenechloride, chloroform, ethyl acetate and THF is used along with a basesuch as triethylamine, diisopropylethylamine, pyridine, lutidine and2,4,6-trimethylpyridine, and the compound of the general formula (6) ispreferably reacted with methanesulfonyl chloride or anhydroustrifluoromethanesulfonate at −45° C. to room temperature.

The brominated or iodized compound is synthesized by reacting themethanesulfonyloxylated product obtained in the above process withsodium bromide, sodium iodide, potassium bromide, potassium iodide,lithium bromide or lithium iodide at room temperature to refluxtemperature in a solvent such as toluene, benzene or THF.

In the synthetic pathway 5, the compound represented by the followinggeneral formula (26-1):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reacting the compound of the general formula (25) with acompound represented by the following general formula (27):PO(OR₆)₃   (27)(wherein R₆ is as defined above) (Step W-1)

This reaction is preferably carried out in the absence of solvent andusing the compound of the general formula (27) as a solvent and ispreferably carried out at 100 to 150° C. or at reflux temperature.

In the synthetic pathway 5, the compound represented by the followinggeneral formula (26-2):

(wherein V is a fluorinated or unfluorinated methylene group; and R₁,R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can be obtained byreacting the compound of the general formula (25) with a compoundrepresented by the following general formula (28):HVPO(OR₆)₂   (28)(wherein R₆ and V are as defined above) in the presence of a base (StepW-2).

This reaction may be carried out in the presence of such a base aslithium diisopropylamide, lithium hexamethyldisilazide and lithiumtetramethylpiperidide in such a reaction solvent as THF and 1,4-dioxaneand may be carried out at a reaction temperature of −78° C. to roomtemperature.

In the synthetic pathway 5, the compound of the general formula (1g) canbe obtained by acidolysis or hydrolysis of the compound of the generalformula (26-1) or (26-2) (Step X).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature. Alternatively, the reaction may use methanol, ethanol,1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may be carriedout at a reaction temperature of 0° C. to reflux temperature, preferably80° C. to 100° C., and in the presence of a base such as an aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.

Of the compounds represented by the general formula (1), those in whichR₅ is a lower alkyl group having 1 to 4 carbon atoms and Y is—CH(OH)CF₂— and which are represented by the following general formula(1h):

(wherein R₁, R₂, R₃, R₄, R₆, X and n are as defined above) can besynthesized through the following synthetic pathway 6:

In the synthetic pathway 6, the compound represented by the followinggeneral formula (29):

(wherein R₁, R₂, R₃, R₄, R₆, R₈, X and n are as defined above) can beobtained by reacting the compound of the general formula (14) with acompound represented by the following general formula (30):HCF₂PO(OR₆)₂   (30)(wherein R₆ is as defined above) in the presence of a base (Step Y).

This reaction may use n-butyllithium, preferably lithiumdiisopropylamide, as a base and 1,4-dioxane or ether, preferably THF, asa solvent and may be carried out at −78° C. to 0° C.

In the synthetic pathway 6, the compound of the general formula (1h) canbe obtained by acidolysis or hydrolysis of the compound of the generalformula (29) (Step Z).

This reaction may be carried out in an inorganic acid or organic acidsuch as acetic acid, hydrochloric acid, hydrobromic acid,methanesulfonic acid and trifluoroacetic acid or in a mixture with anorganic solvent such as methanol, ethanol, THF, 1,4-dioxane and ethylacetate and may be carried out at a reaction temperature of 0° C. toroom temperature. Alternatively, the reaction may use methanol, ethanol,1,4-dioxane, DMSO, DMF or THF as a reaction solvent and may be carriedout at a reaction temperature of 0° C. to reflux temperature, preferably80° C. to 100° C., and in the presence of a base such as an aqueoussolution of sodium hydroxide, potassium hydroxide or lithium hydroxide.

Of the compounds represented by the general formula (1), those in whichR₅ is hydrogen and which are represented by the following generalformula (1i):

(wherein R₁, R₂, R₃, R₄, X, Y and n are as defined above) can beobtained by acidolysis or treatment with trimethylsilyl bromide ortrimethylsilyl iodide of the compound represented by the followinggeneral formula (31):

(wherein R₁₀ is a hydrogen atom or a lower alkoxycarbonyl group having 1to 4 carbon atoms ; and R₁, R₂, R₃, R₄, R₆, X, Y and n are as definedabove).

The acidolysis process is preferably carried out in an inorganic acidsuch as hydrochloric acid and hydrobromic acid or in a mixture with anorganic acid such as methanol and ethanol and is preferably carried outat reflux temperature.

Alternatively, the reaction may use acetonitrile or methylene chlorideas a solvent and the compound of the general formula (31) may be treatedwith trimethylsilyl bromide or trimethylsilyl iodide, or the combinationof trimethylsilyl chloride and sodium bromide or sodium iodide. In sucha case, the reaction is preferably carried out at 0° C. to roomtemperature.

The compounds of the respective general formulae in which X is SO or SO₂may also be obtained by oxidation of the corresponding compounds inwhich X is S.

Such a reaction may use 1,4-dioxane, DMSO, DMF, THF, methylene chlorideor chloroform as a reaction solvent and potassium permanganate,m-chlorobenzoic acid or aqueous hydrogen peroxide as an oxidizing agentand is preferably carried out at 0° C. to reflux temperature, preferablyat room temperature.

EXAMPLES

The present invention will now be described with reference to specificexamples, which are not intended to limit the scope of the invention inany way.

Reference Example 12-chloro-4-[(3-trifluoromethyl)phenylthio]benzaldehyde

To a DMF solution (20 mL) of 2-chloro-4-fluorobenzaldehyde(1.15 g) and3-(trifluoromethyl)thiophenol(1.33 g), potassium carbonate (2.76 g) wasadded and the mixture was stirred for 1 hour at, 120° C. Subsequently,the reaction mixture was poured into water and was extracted with ethylacetate. The extract was washed sequentially with water and a saturatedaqueous solution of sodium chloride and the organic phase was dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand the resulting residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=10:1). This gave the desiredproduct as a pale yellow oil (1.96 g).

Reference Examples 2 through 57

In a similar manner to Reference Example 1, different thiophenols andphenols were used to synthesize the different compounds shown in Table 1below. TABLE 1

Reference Examples R1 R2 R3 R4 X 2 Cl c-Cl H Cl O 3 t-Bu H H H O 4 Me HH H O 5 i-Pr c-i-Pr H Cl O 6 C₅H₁₁ H H H O 7 C₇H₁₅ H H H O 8 CF₃ H H H O9 CF₃ H OMe H O 10 CF₃ H H OMe O 11 CF₃ H H OCH₂Ph O 12 CF₃ H CF₃ H O 13CF₃ H H CF₃ O 14 CF₃ c-CF₃ H H O 15 CF₃ c-CF₃ H Cl O 16 CF₃ b-Cl H H O17 CF₃ a-Cl H H O 18 CF₃ d-Cl H H O 19 CF₃ c-MeO H Cl O 20 Ph(CH₂)₂ H HCl O 21 Ph(CH₂)₂ H H CF₃ O 22 Ph(CH₂)₂ c-CF₃ H H O 23 Ph(CH₂)₂ c-CF₃ HCl O 24 Ph(CH₂)₂ c-Ph(CH₂)₂ H H O 25 Ph(CH₂)₂ c-Ph(CH₂)₂ H CF₃ O 26Ph(CH₂)₂ c-Ph(CH₂)₂ H Cl O 27 CF₃ c-NO₂ H H O 28 CF₃ H Cl H O 29 CF₃ H HCl O 30 i-PrO c-iPr H Cl O 31 i-PrO c-iPr H H O 32 PhO H H Cl O 33PhCH₂O H H H O 34 PhCH₂O H H Br O 35 PhCH₂O H H SMe O 36 PhCH₂O H H Me O37 PhCH₂O H H Et O 38 PhCH₂O i-Cl H Cl O 39 PhCH₂O H H CF₃ O 40 PhCH₂O HH Ph O 41 PhCH₂O c-PhCH₂O H Cl O 42 PhCH₂O c-PhCH₂O H H O 43 PHCH₂Oc-PhCH₂O H i-Pr O 44 MeO i-CF₃ H H O 45 MeS H H H O 46 PhCH₂S H H H O 47PhCH₂S H H Cl O 48 Cl c-Cl H H S 49 CF₃ c-CF₃ H Cl S 50 CF₃ c-CF₃ H H S51 CF₃ H H H S 52 CF₃ H H CF₃ S 53 MeO H H Cl S 54 MeO H H H S 55 MeO HH CF₃ S 56 PhCH₂O H H Cl O 57 PhCH₂O H H i-Pr O

Reference Example 58 2-fluoro-4-[(3-trifluoromethyl)phenoxy]benzaldehyde

3-(trifluoromethyl)phenylboric acid (1.03 g) and2-fluoro-4-hydroxybenzaldehyde (760 mg) were dissolved in methylenechloride (20mL). While the mixture was stirred, copper acetate (985 mg),molecular sieve 4A (800 mg) and triethylamine (3.76 mL) were added tothe mixture. An equal amount of copper acetate was added after 6 hoursand after 24 hours. After 48 hours of stirring, the insoluble materialswere removed by filtration and the filtrate was poured in water and wasextracted with ethyl acetate. The extract was washed sequentially withwater and a saturated aqueous solution of sodium chloride, and theorganic phase was dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure and the resulting residue waspurified on a silica gel column chromatography (hexane:ethyl acetate=7:1then 2:1). This gave the desired product as a pale yellow oil (265 mg).

Reference Example 59 4-[(3-benzyloxy)phenoxy]-2-fluorobenzaldehyde

In a similar manner to Reference Example 58, 3-benzyloxyphenylboric acidand 2-fluoro-4-hydroxybenzaldehyde were used to obtain the desiredproduct as a colorless oil.

Reference Example 60 Ethyl2′-chloro-4′-[(3-trifluoromethyl)phenylthio]cinnamate

At 0° C. and under a stream of argon gas, 60% sodium hydride (272 mg)was added to a THF solution (30 mL) of ethyl diethylphosphonoacetate(1.35 mL). The mixture was stirred for 30 min and a THF solution (15 mL)of the compound of Reference Example 1 (1.96 g) was added dropwise. Themixture was stirred for 2 hours while kept at the same temperature. Thiswas followed by addition of water and extraction with ethyl acetate. Theextract was washed sequentially with water and a saturated aqueoussolution of sodium chloride, and the organic phase was dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified on a silica gel column chromatography(hexane:ethyl acetate=10:1). This gave the desired product as acolorless oil (1.72 g).

Reference Examples 61 through 118

In a similar manner to Reference Example 60, the compounds of ReferenceExamples 2 through 59 were used to synthesize the compounds shown inTable 2 below. TABLE 2

Reference Examples R1 R2 R3 R4 X 61 Cl c-Cl H Cl O 62 t-Bu H H H O 63 MeH H H O 64 i-Pr c-i-Pr H Cl O 65 C₅H₁₁ H K H O 66 C₇H₁₅ H H H O 67 CF₃ HH H O 68 CF₃ H OMe H O 69 CF₃ H H OMe O 70 CF₃ H H OCH₂Ph O 71 CF₃ H CF₃H O 72 CF₃ H H CF₃ O 73 CF₃ c-CF₃ H H O 74 CF₃ c-CF₃ H Cl O 75 CF₃ b-ClH H O 76 CF₃ a-Cl H H O 77 CF₃ d-Cl H H O 78 CF₃ c-MeO H Cl O 79Ph(CH₂)₂ H H Cl O 80 Ph(CH₂)₂ H H CF₃ O 81 Ph(CH₂)₂ c-CF₃ H H O 82Ph(CH₂)₂ c-CF₃ H Cl O 83 Ph(CH₂)₂ c-Ph(CH₂)₂ H H O 84 Ph(CH₂)₂c-Ph(CH₂)₂ H CF₃ O 85 Ph(CH₂)₂ c-Ph(CH₂)₂ H Cl O 86 CF₃ H H F O 87PhCH₂O H H F O 88 CF₃ H Cl H O 89 CF₃ H H Cl O 90 i-PrO c-iPr H Cl O 91i-PrO c-iPr H H O 92 PhO H H Cl O 93 PhCH₂O H H H O 94 PhCH₂O H H Br O95 PhCH₂O H H SMe O 96 PhCH₂O H H Me O 97 PhCH₂O H H Et O 98 PhCH₂O c-ClH Cl O 99 PhCH₂O H H CF₃ O 100 PhCH₂O H H Ph O 101 PhCH₂O c-PhCH₂O H ClO 102 PhCH₂O c-PhCH₂O H H O 103 PhCH₂O c-PhCH₂O H i-Pr O 104 MeO c-CF₃ HH O 105 MeS H H H O 106 PhCH₂S H H H O 107 PhCH₂S H H Cl O 108 Cl c-Cl HH S 109 CF₃ c-CF₃ H Cl S 110 CF₃ c-CF₃ H H S 111 CF₃ H H H S 112 CF₃ H HCF₃ S 113 MeO H H Cl S 114 MeO H H H S 115 MeO H H CF₃ S 116 CF₃ c-NO₂ HH O 117 PhCH₂O H H Cl O 118 PhCH₂O H H i-Pr O

Reference Example 119 Methyl 4′-(3-ethylphenoxy)cinnamate

To a DMF solution (50 mL) of 3-ethylphenol (1.13 g) and methyl4′-fluorocinnamate (834 mg), potassium carbonate (1.92 g) was added andthe mixture was stirred for 8 hours at 140° C. The reaction mixture waspoured into water and was extracted with ethyl acetate. The extract waswashed sequentially with water and a saturated aqueous solution ofsodium chloride and the organic phase was dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and theresulting residue was purified on a silica gel column chromatography(hexane:ethyl acetate=30:1). This gave the desired product as a yellowoil (540 mg).

Reference Example 120 Methyl 4′-(3-isobutylphenoxy)cinnamate

To a DMF solution (10 mL) of 3-isobutylphenol (451 mg) and methyl4′-fluorocinnamate (541 mg), potassium carbonate (622 mg) was added andthe mixture was stirred for 8 hours at 140° C. The reaction mixture waspoured into water and was extracted with ethyl acetate. The extract waswashed sequentially with water and a saturated aqueous solution ofsodium chloride and the organic phase was dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and theresulting residue was purified on a silica gel column chromatography(hexane:ethyl acetate=30:1). This gave the desired product as a yellowoil (278 mg).

Reference Example 121 Ethyl 4′-[(3-phenoxymethyl)phenoxy]cinnamate

The compound of Reference Example 63 (2.82 g) was dissolved intetrachlorocarbon (50 mL). To this solution, N-bromosuccinimide (2.31 g)was added and the mixture was stirred while heated and exposed to light.After 24 hours, the solvent was removed under reduced pressure and theresulting residue was extracted with ethyl acetate. The extract waswashed sequentially with water and a saturated aqueous solution ofsodium chloride and the organic phase was dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and theresulting residue was purified on a silica gel column chromatography(hexane:ethyl acetate=6:1). This gave ethyl4′-[(3-bromomethyl)phenoxy]cinnamate as a yellow oil (1.30 g). Theresultant brominated product (1.24 g) was dissolved in DMF (25 mL). Tothis solution, phenol (380 mg) and potassium carbonate (500 mg) wereadded and the mixture was stirred for 3 hours at 60° C. The reactionmixture was poured into water and was extracted with ethyl acetate. Theextract was washed sequentially with water and a saturated aqueoussolution of sodium chloride and the organic phase was dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand the resulting residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=4:1). This gave the desired productas a colorless oil (1.30 g).

Reference Example 122 Ethyl2′-chloro-4′-(3-trifluoromethylphenylthio)dihydrocinnamate

The compound of Reference Example 60 (1.72 g) was dissolved in ethanol(70 mL). While the solution was stirred at 0° C., bismuth chloride (703mg) was added. Subsequently, sodium borohydride (673 mg) was added insmall portions and the mixture was stirred for 1 hour at thistemperature and 3 hours at room temperature. Ice water was added and thecrystallized insoluble inorganic residue was removed by filtrationthrough Celite. The filtrate was extracted with ethyl acetate and theextract was washed sequentially with water and a saturated aqueoussolution of sodium chloride. The organic phase was then dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give the desired product as a colorless oil (1.50 g) (Process A).

Reference Example 123 Methyl 4′-(3-ethylphenoxy)dihydrocinnamate

The compound of Reference Example 119 (540 mg) was dissolved in ethanol(20 mL) and 10%-Pd/C (80.0 mg) was added. Under a stream of hydrogen,the mixture was stirred at room temperature for 3 hours. The catalystwas removed by filtration and the filtrate was concentrated underreduced pressure to give the desired product as a colorless oil (ProcessB).

Reference Example 124 Ethyl2′-benzyloxy-4′-[(3-trifluoromethyl)phenoxy]dihydrocinnamate

The compound of Reference Example 70 (2.29 mg) was dissolved in ethylacetate (30 mL) and 5%-Pd/C-ethylenediamine complex (230 mg) was added.Under a stream of hydrogen, the mixture was stirred at room temperaturefor 3.5 hours. The catalyst was removed by filtration and the solventwas removed under reduced pressure to give the desired product as a paleyellow oil (2.30 g) (Process C).

Reference Example 125 Methyl 4′-[(3-methylthio)phenoxy]dihydrocinnamate

Under a stream of argon gas, the compound of Reference Example 105 (4.07g) was dissolved in methanol (50 mL). While the solution was stirred at10° C., magnesium (1.00 g) was added. The mixture was stirred for 3hours while kept at this temperature, and diluted hydrochloric acid wasadded. The mixture was extracted with ethyl acetate and was washedsequentially with water and a saturated aqueous solution of sodiumchloride. The organic phase was then dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give thedesired product as a colorless oil (3.70 g) (Process D).

Reference Examples 126 through 182

Similarly, the compounds of Reference Examples 61 through 69, 71 through104, 106 through 116, 117 and 118, and 120 and 121 were used tosynthesize the compounds shown in Table 3 below. TABLE 3

Reference Examples R1 R2 R3 R4 X Process 126 Cl c-Cl H Cl O A 127 t-Bu HH H O B 128 Me H H H O B 129 i-Pr c-i-Pr H Cl O A 130 C₅H₁₁ H H H O B131 C₇H₁₅ H H H O B 132 CF₃ H H H O B 133 CF₃ H OMe H O B 134 CF₃ H HOMe O B 135 CF₃ H CF₃ H O B 136 CF₃ H H CF₃ O B 137 CF₃ c-CF₃ H H O B138 CF₃ c-CF₃ H Cl O B 139 CF₃ b-Cl H H O A 140 CF₃ a-Cl H H O A 141 CF₃d-Cl H H O A 142 CF₃ c-MeO H Cl O B 143 Ph(CH₂)₂ H H Cl O A 144 Ph(CH₂)₂H H CF₃ O B 145 Ph(CH₂)₂ c-CF₃ H H O B 146 Ph(CH₂)₂ c-CF₃ H Cl O A 147Ph(CH₂)₂ c-Ph(CH₂)₂ H H O B 148 Ph(CH₂)₂ c-Ph(CH₂)₂ H CF₃ O B 149Ph(CH₂)₂ c-Ph(CH₂)₂ H Cl O A 150 CF₃ H H F O B 151 PhCH₂O H H F O A 152PhOCH₂ H H H O A 153 CF₃ H Cl H O A 154 CF₃ H H Cl O A 155 i-PrO c-iPr HCl O C 156 i-PrO c-iPr H H O B 157 PhO H H Cl O A 158 PhCH₂O H H H O A159 PhCH₂O H H Br O A 160 PhCH₂O H H SMe O A 161 PhCH₂O H H Me O A 162PhCH₃O H H Et O A 163 PhCH₂O c-Cl H Cl O A 164 PhCH₂O H H CF₃ O A 165PhCH₂O H H Ph O A 166 PhCH₂O c-PhCH₂O H Cl O A 167 PhCH₂O c-PhCH₂O H H OA 168 PhCH₂O c-PhCH₂O H i-Pr O A 169 MeO o-CF₃ H H O B 170 PhCH₂S H H HO A 171 PhCH₂S H H Cl O A 172 Cl H H H S D 173 CF₃ c-CF₃ H Cl S A 174CF₃ c-Me H H S D 175 CF₃ H H H S A 176 CF₃ H H CF₃ S A 177 MeO H H Cl SA 178 MeO H H H S A 179 MeO H H CF₃ S A 180 i-Bu H H H O B 181 PhCH₂O HH Cl O A 182 PhCH₂O H H iPr O A

Reference Example 183 Ethyl4′-[3-chloro-5-(trifluoromethyl)phenoxy]dihydrocinnamate

The compound of Reference Example 116 was reacted in the same manner asin Reference Example 124 to obtain ethyl4′-[3-amino-5-(trifluoromethyl)phenoxy]dihydrocinnamate. An MeCNsolution (15 mL) containing this compound (1.27 g) was added to an MeCNsolution (40 mL) containing copper chloride (725 mg) and tBuONO (0.51mL). This mixture was stirred for 3 hours at room temperature, followedby addition of water and extraction with ethyl acetate. The extract wasthen washed with water and the organic phase was dried over anhydroussodium sulfate. The solvent was removed by distillation and the residuewas purified on a silica gel column chromatography (hexane:ethylacetate=20:1). This gave the desired product as a pale yellow oil (1.10g).

Reference Example 184 Benzyl4′-[3-benzyloxy-5-(trifluoromethyl)phenoxy]dihydrocinnamate

The compound of Reference Example 169 (840 mg) was dissolved inmethylene chloride (20 mL). While the solution was stirred at 0° C., a 1mol/L methylene chloride solution of tribromoboron (3.42 mL) was addeddropwise. The reaction mixture was stirred at room temperatureovernight. Subsequently, ice water was added, and the mixture wasextracted with ethyl acetate and was washed sequentially with water anda saturated aqueous solution of sodium chloride. The organic phase wasdried over anhydrous sodium sulfate. The solvent was then removed underreduced pressure to give4′-(3-trifluoromethyl-5-hydroxyphenoxy)dihydrocinnamic acid as a palebrown powder (750 mg). The resulting powder was dissolved in DMF (50mL). To this solution, potassium carbonate (1.04 g) and benzyl bromide(0.602 mL) were added and the mixture was stirred at room temperaturefor 8 hours. Subsequently, the reaction mixture was poured into icewater, and the mixture was extracted with ethyl acetate and was washedsequentially with water and a saturated aqueous solution of sodiumchloride. The organic phase was then dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give thedesired product as a brown oil.

Reference Example 185 Benzyl4′-(3-benzyloxyphenylthio)-2′-chlorodihydrocinnamate

Using the compound of Reference Example 177, the reaction was carriedout in the same manner as in Reference Example 184 to give the desiredproduct as a yellow oil.

Reference Example 186 Benzyl 4′-(3-benzyloxyphenylthio)-dihydrocinnamate

Using the compound of Reference Example 178, the reaction was carriedout in the same manner as in Reference Example 184 to give the desiredproduct as a yellow oil.

Reference Example 187 Ethyl4′-[3-benzyloxy-5-(trifluoromethyl)phenoxy]-2′-chlorodihydrocinnamate

In the same manner as in Reference Example 184, the compound ofReference Example 142 was reacted to give2′-chloro-4′-(3-trifluoromethyl-5-hydroxyphenoxy)dihydrocinnamic acid.This cinnamic acid (1.47 g) was dissolved in ethanol (10 mL). While thissolution was stirred at 0° C., thionyl chloride (3 mL) was addeddropwise. The mixture was stirred for 2 hours while kept at thistemperature. Subsequently, the solvent was removed under reducedpressure and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=10:1 and then 6:1) to give ethyl2′-chloro-4′-(3-trifluoromethyl-5-hydroxyphenoxy)dihydrocinnamate as acolorless oil (1.38 g). In the same manner as in Reference Example 184,the resulting ester was converted into a benzyl ether using potassiumcarbonate and benzyl bromide. This gave the desired product as acolorless oil.

Reference Example 188 Ethyl4′-(3-benzyloxyphenylthio)-2′-trifluoromethyldihydrocinnamate

Using the compound of Reference Example 179, the reaction was carriedout in the same manner as in Reference Example 187 to give the desiredproduct as a colorless oil.

Reference Example 1894′-[(3-benzyloxy)phenylthio]-2′-chlorodihydrocinnamyl alcohol

The compound of Reference Example 185 (7.40 g) was dissolved in THF (100mL). While this solution was stirred at 0° C., lithium aluminum hydride(500 mg) was added. After 10 min, a 20% aqueous solution of NaOH wasadded and the crystallized insoluble inorganic residue was removed byfiltration through Celite. The filtrate was extracted with ethyl acetateand the extract was washed sequentially with water and a saturatedaqueous solution of sodium chloride. The organic phase was then driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure to give the desired product as a colorless oil (6.37 g).

Reference Examples 190 through 251

In a similar manner to Reference Example 189, the compounds of ReferenceExamples 122 through 141, 143 through 168, 170 through 177 and 180through 188 were used to synthesize the compounds shown in Table 4below. TABLE 4

Reference Examples R1 R2 R3 R4 X 190 Cl c-Cl H Cl O 191 t-Bu H H H O 192Me H H H O 193 i-Pr c-i-Pr H Cl O 194 C₅H₁₁ H H H O 195 C₇H₁₅ H H H O196 CF₃ H H H O 197 CF₃ H OMe H O 198 CF₃ H H OMe O 199 CF₃ H CF₃ H O200 CF₃ H H CF₃ O 201 CF₃ c-CF₃ H H O 202 CF₃ c-CF₃ H Cl O 203 CF₃ b-ClH H O 204 CF₃ a-Cl H H O 205 CF₃ d-Cl H H O 206 CF₃ c-PHCH₂O H Cl O 207Ph(CH₂)₂ H H Cl O 208 Ph(CH₂)₂ H H CF₃ O 209 Ph(CH₂)₂ c-CF₃ H H O 210Ph(CH₂)₂ c-CF₃ H Cl O 211 Ph(CH₂)₂ c-Ph(CH₂)₂ H H O 212 Ph(CH₂)₂c-Ph(CH₂)₂ H CF₃ O 213 Ph(CH₂)₂ c-Ph(CH₂)₂ H Cl O 214 CF₃ H H F O 215PhCH₂O H H F O 216 CF₃ H H Cl S 217 Et H H H O 218 CF₃ H H PhCH₂O O 219CF₃ H Cl H O 220 CF₃ H H Cl O 221 i-PrO c-iPr H Cl O 222 i-PrO c-iPr H HO 223 PhO H H Cl O 224 PhCH₂O H H H O 225 PhCH₂O H H Br O 228 PhCH₂O H HSMe O 227 PhCH₂O H H Me O 228 PhCH₂O H H Et O 229 PhCH₂O c-Cl H Cl O 230PhCH₂O H H CF₃ O 231 PhCH₂O H H Ph O 232 PhCH₂O c-PhCH₂O H Cl O 233PhCH₂O c-PhCH₂O H H O 234 PhCH₂O c-PhCH₂O H i-Pr O 235 PhCH₂O c-CF₃ H HO 238 PhCH₂S H H H O 237 PhCH₂S H H Cl O 239 Cl H H H S 238 CF₃ c-CF₃ HCl S 240 CF₃ c-Me H H S 241 CF₃ H H H S 242 CF₃ H H CF₃ S 243 MeO H H ClS 244 PhCH₂O H H H S 245 PhCH₂O H H CF₃ S 246 i-Bu H H H O 247 PhOCH₂ HH H O 248 CF₃ c-Cl H H O 249 MeS H H H O 250 PhCH₂O H H Cl O 251 PhCH₂OH H i-Pr O

Reference Example 2524′-(3-benzyloxyphenylthio)-2′-chloro-dihydrocinnamyl iodide

The compound of Reference Example 189 (1.38 g) was dissolved in THF (20mL). While this solution was stirred at 0° C., imidazole (545 mg),triphenylphosphine (2.10 g) and iodine (2.00 g) were added. The mixturewas stirred 2 hours at this temperature and subsequent 1.5 hours at roomtemperature, and additional imidazole (160 mg), triphenyl phosphine (600mg) and iodine (500 mg) were added. The mixture was stirred overnight,followed by the addition of water and then sodium thiosulfate. Thereaction mixture was then extracted with ethyl acetate and the extractwas washed sequentially with water and a saturated aqueous solution ofsodium chloride. The organic phase was then dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified on a silica gel column chromatography (hexane:ethylacetate=50:1) to give the desired product as a colorless oil (1.55 g).

Reference Examples 253 through 314

In a similar manner to Reference Example 252, the compounds of ReferenceExamples 190 through 251 were used to synthesize the compounds shown inTable 5 below. TABLE 5

Reference Examples R1 R2 R3 R4 X 253 Cl c-Cl H Cl O 254 t-Bu H H H O 255Me H H H O 256 i-Pr c-i-Pr H Cl O 257 C₅H₁₁ H H H O 258 C₇H₁₅ H H H O259 CF₃ H H H O 260 CF₃ H OMe H O 261 CF₃ H H OMe O 262 CF₃ H CF₃ H O263 CF₃ H H CF₃ O 264 CF₃ c-CF₃ H H O 265 CF₃ c-CF₃ H Cl O 266 CF₃ b-ClH H O 267 CF₃ s-Cl H H O 268 CF₃ d-Cl H H O 269 CF₃ c-PhCH₂O H Cl O 270Ph(CH₂)₂ H H Cl O 271 Ph(CH₂)₂ H H CF₃ O 272 Ph(CH₂)₂ c-CF₃ H H O 273Ph(CH₂)₂ c-CF₃ H Cl O 274 Ph(CH₂)₂ c-Ph(CH₂)₂ H H O 275 Ph(CH₂)₂c-Ph(CH₂)₂ H CF₃ O 276 Ph(CH₂)₂ c-Ph(CH₂)₂ H Cl O 277 CF₃ H H F O 278PhCH₂O H H F O 279 CF₃ H H Cl S 280 Et H H H O 281 CF₃ H H PhCH₂O O 282CF₃ H Cl H O 283 CF₃ H H Cl O 284 i-PrO c-iPr H Cl O 285 i-PrO c-iPr H HO 286 PhO H H Cl O 287 PhCH₂O H H H O 288 PhCH₂O H H Br O 289 PhCH₂O H HSMe O 290 PhCH₂O H H Me O 291 PhCH₂O H H Et O 292 PhCH₂O c-Cl H Cl O 293PhCH₂O H H CF₃ O 294 PhCH₂O H H Ph O 295 PhCH₂O c-PhCH₂O H Cl O 296PhCH₂O c-PhCH₂O H H O 297 PhCH₂O c-PhCH₂O H i-Pr O 298 PhCH₂O c-CF₃ H HO 299 PhCH₂S H H H O 300 PhCH₂S H H Cl O 301 Cl H H H S 302 CF₃ c-CF₃ HCl S 303 CF₃ c-Me H H S 304 CF₃ H H H S 305 CF₃ H H CF₃ S 306 MeO H H ClS 307 PhCH₂O H H H S 308 PhCH₂O H H CF₃ S 309 i-Bu H H H O 310 PhOCH₂ HH H O 311 CF₃ c-Cl H H O 312 MeS H H H O 313 PhCH₂O H H Cl O 314 PhCH₂OH H i-Pr O

Reference Example 315 4-(3,5-dichlorophenoxy)benzyl bromide

Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction wascarried out in the same manner as in Reference Example 1 to obtain4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure asin Reference Example 189 was followed using sodium borohydride in placeof the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzylalcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide(2.75 g), was dissolved in methylene chloride (30 mL). While thissolution was stirred at 0° C., triphenyl phosphine (2.17 g) was added.The mixture was stirred at 0° C. for 1 hour and at room temperature forthe subsequent 30 min. The solvent was removed under reduced pressureand the residue was purified on a silica gel column chromatography(hexane:ethyl acetate=20:1) to give the desired product as a colorlessoil (3.12 g).

Reference Example 316 1-iodopropyl-4-[(3-methanesulfinyl)phenoxy]benzene

The compound of Reference Example 312 (1.80 g) was dissolved inmethylene chloride (30 mL). While this solution was stirred at 0° C.,m-chlorobenzoic acid (770 mg) was added in small portions. The mixturewas stirred at this temperature for 1 hour and at room temperature forthe subsequent 24 hours. Following addition of water, the mixture wasextracted with ethyl acetate and the extract was washed sequentiallywith a saturated aqueous solution of sodium carbonate and a saturatedaqueous solution of sodium chloride. The organic phase was then driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=2:1 and then 1:2) to give thedesired product as a yellow oil (1.29 g).

Reference Example 317 4′-(3-benzyloxyphenylthio)-2′-chlorophenethyliodide

Reference Example 317-1 2′-chloro-4′-(3-methoxyphenylthio)benzyl cyanide

The compound of Reference Example 53 was treated in the same manner asin Reference Example 189 to obtain an alcohol. The alcohol (5.64 g) wasdissolved in methylene chloride (100 mL) and phosphorus tribromide (2.25mL) was added dropwise. Following stirring at room temperature for 1hour, ice water was added and the mixture was extracted with ethylacetate. The extract was washed sequentially with water and an aqueoussolution of sodium chloride, and the organic phase was dried overanhydrous sodium sulfate. The solvent was removed by distillation toobtain a pale yellow oil. The oil and potassium cyanide (1.56 g) weredissolved in a mixture of DMSO (25 mL) and water (10 mL) and thesolution was stirred at 90° C. for 5 hours. Following addition of water,the mixture was extracted with ethyl acetate and the extract was washedsequentially with water and a saturated aqueous solution of sodiumchloride. The organic phase was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation and the residue was purified on asilica gel column chromatography (hexane:ethyl acetate=10:1) to give thedesired cyano-product as a pale yellow oil (3.81 g).

Reference Example 317-2 Ethyl2′-chloro-4′-(3-methoxyphenylthio)phenylacetate

The cyano-product (3.81 g) and potassium hydroxide (3.68 g) were addedto a mixture of ethanol (80 mL) and water (10 mL), and the solution wasrefluxed for 6 hours. Subsequently, the solution was allowed to cool andthe insoluble material was removed by filtration. The filtrate wasneutralized with diluted hydrochloric acid. This mixture was extractedwith ethyl acetate and the extract was washed sequentially with waterand a saturated aqueous solution of sodium chloride. The organic phasewas then dried over anhydrous sodium sulfate. The solvent was removed bydistillation and ethanol (50 mL) and thionyl chloride (2 mL) were addedto the resulting residue. This mixture was stirred at room temperaturefor 1 hour and the solvent was removed by distillation. The resultingresidue was purified on a silica gel column chromatography (hexane:ethylacetate=10:1) to give the ethyl ester product as a colorless oil (3.89g).

Reference Example 317-3 4′-(3-benzyloxyphenylthio)-21-chlorophenethyliodide

The ethyl ester was reacted in the same manner as in Reference Example187 to obtain ethyl 4′-(3-benzyloxyphenylthio)-2′-chlorophenyl-acetate.The product was reduced as in Reference Example 189 to obtain analcohol, which in turn was reacted in the same manner as in ReferenceExample 252 to give the desired product as a colorless oil.

Reference Example 3181-(3-benzyloxyphenylthio)-3-chloro-4-iodobutylbenzene

Reference Example 318-1 4-(3-benzyloxyphenylthio)-2-chlorophenethylaldehyde

Ethyl 4′-(3-benzyloxyphenylthio)-2′-chlorophenylacetate obtained inReference Example 317-3 was subjected to alkali-hydrolysis. Theresulting product was condensed with N,O-dimethylhydroxylamine to forman amide product, which in turn was reduced in the same manner as inReference Example 189 to give the desired aldehyde product as a yellowoil.

Reference Example 318-2 Ethyl4-[(3-benzyloxyphenylthio)-2-chlorophenyl]butyrate

The compound of Reference Example 318-1 was reacted in the same manneras in Reference Example 60 and the unsaturated bonds of the resultingproduct were reduced in the same manner as in Reference Example 122 togive the desired ethyl butyrate derivative.

Reference Example 318-31-(3-benzyloxyphenylthio)-3-chloro-4-iodobutylbenzene

The compound of Reference Example 318-2 was reacted in the same manneras in Reference Example 189 to obtain an alcohol product, which in turnwas reacted in the same manner as in Reference Example 252 to give thedesired product as a colorless oil.

Reference Example 319 4′-[(3-benzyloxy)phenoxy]-2′-chlorophenethyliodide

The compound of Reference Example 56 was reacted in the same manner asin Reference Example 317 to obtain the desired product as a yellow oil.

Reference Example 3204-[(3-benzyloxy)phenoxy]-2-chloro-1-iodobutylbenzene

The compound of Reference Example 56 was reacted in the same manner asin Reference Example 318 to obtain the desired product as a pale yellowoil.

Reference Example 321 4′-benzyloxydihydrocinnamyl iodide

4′-benzyloxydihydrocinnamyl alcohol was reacted in the same manner as inReference Example 252 to obtain the desired product as a yellow powder.

Reference Example 322 4′-(3-benzyloxyphenylthio)-2′-chlorobenzyl bromide

In place of 2-chloro-4-fluorobenzaldehyde, 2-chloro-4-fluorobenzonitrilewas reacted in the same manner as in Reference Example 1 to obtain2-chloro-4-(3-methoxyphenylthio)benzonitrile. Following the sameprocedure as in Reference Example 317-2, this product was hydrolyzedand, then, following the same procedure as in Reference Example 187, themethoxy group was decomposed and esterified to convert the product intoa benzyl ether. The product was then reacted in the same manner as inReference Example 189 to be converted into an alcohol. Subsequently, theproduct was reacted with carbon tetrabromide in the same manner as inReference Example 315 to obtain the desired product as a colorless oil.

Reference Example 3232′-chloro-4′-(4-trifluoromethylphenoxy)dihydrocinnamyl iodide

Using p-trifluoromethylphenol, the reaction was carried out in the samemanner as in Reference Example 1 to obtain an aldehyde. Following thesame procedure as in Reference Example 60, the aldehyde was subjected toHorner-Emmons reaction. Subsequently, following the same procedure as inReference Example 123, the resulting product was reduced and, then,following the same procedure as in Reference Example 189, the reducedproduct was converted into an alcohol. Subsequently, the alcohol wasiodized in the same manner as in Reference Example 252 to give thedesired product as a colorless oil.

MS(EI+): 440([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 2.12-2.19(2H, m), 2.85(2H, t, J=7.3 Hz),3.21(2H, t, J=7.3 Hz), 6.90(1H, dd, J=2.5, 8.6 Hz), 7.04-7.08(3H, m),7.23-7.27(1H, m), 7.60(2H, d, J=8.6 Hz).

Reference Example 3242′-chloro-4′-(2-trifluoromethylphenoxy)dihydrocinnamyl iodide

Using o-trifluoromethylphenol, the reaction was carried out in the samemanner as in Reference Example 232 to obtain the desired product as acolorless oil.

MS(EI+): 440 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 2.11-2.18(2H, m), 2.83(2H, t, J=7.3 Hz),3.21(2H, t, J=7.3 Hz), 6.88(1H, dd, J=2.5, 8.6 Hz), 6.96(1H, d, J=8.6Hz), 7.04(1H, d, J=2.5 Hz), 7.18-7.26(2H, m), 7.49(1H, t, J=8.6 Hz),7.68(1H, d, J=8.0 Hz).

Reference Example 325 4-(4-benzyloxyphenylthio)-2-chlorobenzaldehyde

p-hydroxythiophenol (2.12 g) was dissolved in N,N-dimethylformamide (40mL). To this solution, 2-chloro-4-fluorobenzaldehyde (2.66 g) andpotassium carbonate (4.64 g) were added and the mixture was stirred for2 hours at 50° C. Subsequently, benzyl bromide (4.00 mL) was added andthe mixture was stirred for 1.5 hours at 50° C. and then for 2.5 hoursat 70° C. The reaction mixture was extracted with ethyl acetate and theextract was washed sequentially with water and a saturated aqueoussolution of sodium chloride. The organic phase was then dried overanhydrous sodium sulfate. Following addition of water, the solvent wasremoved by distillation and the residue was purified on a silica gelcolumn chromatography (hexane:ethyl acetate=10:1). This gave the desiredproduct as a colorless solid (5.70 g).

¹H-NMR(400 MHz, CDCl₃) δ 5.12(2H, s), 6.96-7.03(3H, m), 7.06 (2H, m),7.38-7.50(6H, m), 8.56(1H, d, J=8.6 Hz), 10.33(1H, s).

Reference Example 3264′-(4-benzyloxyphenylthio)-2′-chlorophenethylaldehyde

To an ice-cold tetrahydrofuran solution (160 mL) of(Methoxymethyl)triphenylphosphonium chloride (8.28 g), t-butoxypotassium (2.71 g) was added and the mixture was stirred for 1 hour,followed by addition of the compound of Reference Example 325 (5.70 g)and 1 hour of stirring. Subsequently, water was added to the mixture andthe mixture was extracted with ethyl acetate and the extract was washedsequentially with water and a saturated aqueous solution of sodiumchloride. The organic phase was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation and the resultingresidue was purified on a silica gel column chromatography (hexane:ethylacetate=6:1). This gave the desired vinyl ether product as a pale yellowoil (6.50 g). This product was dissolved in tetrahydrofuran (90 mL). Tothis solution, a 6 mol/L aqueous solution of hydrochloric acid (60 mL)was added and the mixture was stirred for 5 hours at 60° C.Subsequently, the reaction mixture was extracted with ethyl acetate. Theextract was washed sequentially with water and a saturated aqueoussolution of sodium chloride and the organic phase was dried overanhydrous sodium sulfate. Following addition of water, the solvent wasremoved by distillation and the residue was purified on a silica gelcolumn chromatography (hexane:ethyl acetate=9:1). This gave the desiredproduct as a colorless powder (4.48 g).

¹H-NMR(400 MHz, CDCl₃) δ 3.77(2H, d, J=1.8 Hz), 5.09(2H, s),6.97-7.04(3H, m), 7.05-7.10(1H, m), 7.15(1H, d, J=1.8 Hz), 7.32-7.46(7H,m), 9.72(1H, t, J=1.8 Hz).

Reference Example 327 4′-(4-benzyloxyphenylthio)-2′-chlorophenethyliodide

Following the same procedure as in Reference Example 189, the compoundof Example 326 was converted into an alcohol. Then, using the sameprocedure as in Reference Example 252, this alcohol was iodized to givethe desired product as a pale yellow oil.

¹H-NMR(400 MHz, CDCl₃) δ 3.22(2H, t, J=7.3 Hz), 3.30(2H, t, J=7.3 Hz),5.09(2H, s) 6.96-7.02(3H, m), 7.09(2H, d, J=7.9 Hz), 7.33-7.45(7H, m).

Example 1 Ethyl2-t-butoxycarbonylamino-5-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]-2-etoxycarbonylpentanoate

At room temperature and under a stream of argon gas, sodium t-butoxide(490 mg) was added to diethyl 2-t-butoxycarbonylaminomalonate (1.3 mL)in a mixture of THF (35 mL) and DMF (4 mL). This mixture was stirred for20 min at 80° C. and was allowed to cool to room temperature. To thecooled mixture, a THF solution (5 mL) of the compound of ReferenceExample 279 (1.55 g) was added dropwise. The resulting mixture wasrefluxed for 5 hours, was poured into ice water, and was extracted withethyl acetate. The extract was washed sequentially with water and asaturated aqueous solution of sodium chloride. The organic phase wasthen dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=5:1) to give the desired product asa colorless oil (1.87 g).

¹H-NMR(400 MHz, CDCl₃) δ 1.22-1.36(6H, m), 1.42(9H, s), 1.45-1.53(2H,m), 2.37(2H, br), 2.74(2H, t, J=7.8 Hz), 4.23(4H, m), 5.94(1H, s),7.16-7.21(2H, m), 7.36-7.56(5H, m).

<Examples 2 through 67

In a similar manner to Example 1, the halogen derivatives of respectiveReference Examples were used to synthesize the compounds shown in Tables6 and 7 below. TABLE 6

Examples R1 R2 R3 R4 X n Characteristics Yield (%) 2 Cl c-Cl H Cl O 3Colorless oil 74 3 t-Bu H H H O 3 Colorless oil 64 4 CF₃ H H H O 3Colorless oil 100 5 CF₃ H OMe H O 3 Colorless oil 100 6 CF₃ H H OMe O 3Colorless oil 100 7 CF₃ H CF₃ H O 3 Colorless oil 100 8 CF₃ H H CF₃ O 3Colorless oil 92 9 CF₃ c-CF₃ H H O 3 Yellow oil 47 10 CF₃ c-CF₃ H Cl O 3Colorless oil 89 11 CF₃ b-Cl H H O 3 Colorless oil 94 12 CF₃ c-PhCH₂O HCl O 3 Colorless oil 91 13 Ph(CH₂)₂ H H Cl O 3 Colorless oil 83 14Ph(CH₂)₂ H H CF₃ O 3 Colorless oil 90 15 Ph(CH₂)₂ c-CF₃ H H O 3Colorless oil 97 16 Ph(CH₂)₂ c-Ph(CH₂)₂ H H O 3 Colorless oil 95 17Ph(CH₂)₂ c-Ph(CH₂)₂ H CF₃ O 3 Colorless oil 100 18 Ph(CH₂)₂ c-Ph(CH₂)₂ HCl O 3 Colorless oil 98 19 i-PrO o-iPr H Cl O 3 Colorless oil 100 20 PhOH H Cl O 3 Colorless oil 92 21 PhCH₂O H H H O 3 Colorless oil 95 22PhCH₂O H H Br O 3 Colorless oil 100 23 PhCH₂O H H SMe O 3 Colorless oil— 24 PhCH₂O H H Me O 3 Colorless oil 100 25 PhCH₂O H H Et O 3 Colorlessoil 72 26 PhCH₂O H H Cl S 2 Pale yellow oil 100 27 PhCH₂O H H Cl S 3Colorless oil 100 28 PhCH₂O H H Cl S 4 Colorless oil 100 29 PhCH₂O c-CF₃H H O 3 Colorless oil 99 30 Cl H H H S 3 Colorless oil 82 31 CF₃ c-CF₃ HCl S 3 Colorless oil 82 32 Et H H H O 3 Colorless oil 100 33 SOMe H H HO 3 Colorless oil 100 34 Cl c-Cl H H O 1 Colorless oil 56 35 CF₃ H HPhCH₂O O 3 Colorless oil 100 36 PhCH₂O H H Cl O 3 Colorless oil 100 37CF₃ H Cl H O 3 Colorless oil 100 38 CF₃ H H Cl O 3 Colorless oil 100 39PhCH2O H H F O 3 Colorless oil 100 40 CF₃ c-Cl H H O 3 Colorless oil 100- Yield is shown in Tables 8-10 in association with the subsequent step.

TABLE 7

Yield Examples R1 R2 R3 R4 X n Characteristics (%) 41 CF₃ c-Cl H H O 3Pale yellow oil 41 42 CF₃ d-Cl H H O 3 Pale yellow oil 72 43 Ph(CH₂)₂c-CF₃ H Cl O 3 Colorless oil 93 44 PhCH₂O H H Cl O 2 Colorless oil — 45PhCH₂O H H CI O 4 Colorless oil — 46 CF₃ H H F O 3 Colorless oil 100 47PhCH₂O c-PhCH₂O H H O 3 Colorless oil — 48 PhCH₂O c-PhCH₂O H Cl O 3Colorless oil — 49 PhCH₂O c-Cl H Cl O 3 Colorless oil 100 50 PhCH₂O H HCF₃ O 3 Colorless oil 100 51 PhCH₂O H H Ph O 3 Colorless oil — 52 MeS HH H O 3 Colorless oil 83 53 n-C₅H₁₁ H H H O 3 Colorless oil 86 54c-C₇H₁₅ H H H O 3 Colorless oil 88 55 iPr c-iPrO H H O 3 Colorless oil95 56 iPr c-iPr H Cl O 3 Colorless oil 86 57 PhCH₂S H H H O 3 Colorlessoil — 58 PhCH₂S H H Cl O 3 Colorless oil — 59 i-Bu H H H O 3 Colorlessoil 76 60 PhOCH₂ H H H O 3 Colorless oil 100 61 PhCH₂O H H i-Pr O 3Colorless oil — 62 CF₃ H H H S 3 Colorless oil 90 63 CF₃ H H CF₃ S 3Pale yellow oil 53 64 CF₃ c-Me H H S 3 Colorless oil 100 65 MeO H H Cl S3 Colorless oil 87 66 PhCH₂O H H H S 3 Colorless oil — 67 PhCH₂O H H CF₃S 3 Colorless oil 100 68 PhCH₂O H H Cl S 1 Colorless oil 100—Yield is shown in Tables 8-10 in association with the subsequent step.

Example 69 Ethyl5-[(4-benzyloxy)phenyl]-2-t-butoxycarbonylamino-2-ethoxycarbonylpentanoate

The compound of Reference Example 321 was reacted in the same manner asin Example 1 to give the desired product as a pale yellow oil.

¹H-NMR(400 MHz, CDCl₃) δ 1.22(6H, t, J=7.1 Hz), 1.42(9H, s),1.44-1.47(2H, m), 2.31(2H, br s), 2.57(2H, t, J=7.6 Hz), 4.11-4.27(4H,m), 5.03(2H, s), 5.92(1H, br s), 6.88(2H, d, J=8.8 Hz), 7.06(2H, d,J=8.8 Hz), 7.29-7.43(5H, m).

Example 70 Ethyl2-t-butoxycarbonylamino-2-ethoxycarbonyl-5-[4-(3-isopropoxyphenoxy)phenyl]pentanoate

The compound of Example 69 was reduced in the same manner as inReference Example 123. The resulting phenol product (850 mg) wasdissolved in DMF (20 mL). To this solution, 2-iodopropane (0.2 mL) andpotassium carbonate (500 mg) were added and the mixture was stirred for4 hours at 60° C. Following addition of water, the mixture was extractedwith ethyl acetate and the extract was washed sequentially with waterand a saturated aqueous solution of sodium chloride. The organic phasewas dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=4:1) to give the desired product asa colorless oil (760 mg).

¹H-NMR(400 MHz, CDCl₃) δ 1.23(6H, t, J=7.3 Hz), 1.31(6H, d, J=5.9 Hz),1.42(9H, s), 1.45-1.52(2H, m), 2.34(2H, br), 2.61(2H, t, J=7.8 Hz),4.17-4.27(4H, m), 4.50(1H, heptet, 5.9 Hz), 5.94(1H, br s),6.50-6.53(2H, m), 6.59-6.62(1H, m), 6.92(2H, d, J=8.8 Hz), 7.10(2H, d,J=8.8 Hz), 7.18(1H, t, J=8.8 Hz).

Example 71 Ethyl2-t-butoxycarbonylamino-5-[4-(3,5-dichlorophenoxy)phenyl]-2-ethoxycarbonylpentanoate

The compound of Example 69 was reduced in the same manner as inReference Example 123. The resulting phenol product (1.27 g), along with3,5-dichlorophenylboric acid (1.18 g), was dissolved in methylenechloride (30 mL). While this solution was being stirred, copper acetate(676 mg) and triethylamine (0.86 mL) were added. After 16 hours and afurther 8 hours later, the same amount of additional copper acetate wasadded and the mixture was stirred for the subsequent 40 hours.Subsequently, the insoluble material was removed by filtration. Thefiltrate was poured into water and the mixture was extracted with ethylacetate. The extract was washed sequentially with water and a saturatedaqueous solution of sodium chloride. The organic phase was then driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=20:1) to give the desired productas a pale blue oil (333 mg).

Example 72 Ethyl2-t-butoxycarbonylamino-2-ethoxycarbonyl-5-[4-(3-methanesulfonylphenoxy)phenyl]pentanoate

The compound of Example 33 (1.00 g) was dissolved in methylene chloride(30 mL). To this solution, m-chloroperbenzoic acid (610 mg) was addedand the mixture was stirred for 6 hours at room temperature. Followingaddition of water, the mixture was extracted with ethyl acetate and theextract was washed sequentially with a saturated aqueous solution ofsodium hydrogen carbonate and with a saturated aqueous solution ofsodium chloride. The organic phase was dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified on a silica gel column chromatography (hexane:ethylacetate=1:1) to give the desired product as a colorless oil (610 mg).

¹H-NMR(400 MHz, CDCl₃) δ 1.24(6H, t, J=7.3 Hz), 1.42(9H, s),1.47-1.56(2H, m), 2.34(2H, br), 2.64(2H, t, J=7.8 Hz), 3.04(3H, s),4.18-4.26(4H, m), 5.95(1H, br), 6.95(2H, d, J=8.8 Hz), 7.17(2H, t, J=8.8Hz), 7.20-7.30(3H, m), 7.47-7.52(2H, m), 7.62(1H, d, J=8.8 Hz).

Example 73 Ethyl2-t-butoxycarbonylamino-2-ethoxycarbonyl-5-[4-(3-trifluoromethylphenylsulfinyl)]phenylpentanoate

The compound of Example 62 (1.50 g) was dissolved in methylene chloride(80 mL). While this solution was stirred at 0° C., m-chloroperbenzoicacid (450 mg) was added in small portions. The mixture was then stirredfor 1 hour at this temperature and 2 hours at room temperature.Subsequently, water was added to the reaction mixture and the mixturewas extracted with ethyl acetate. The extract was washed sequentiallywith a saturated aqueous solution of sodium hydrogen carbonate and witha saturated aqueous solution of sodium chloride. The organic phase wasdried over anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=1:1) to give the desired product asa yellow oil (1.10 g).

¹H-NMR(400 MHz, CDCl₃) δ 1.18-1.21(6H, m), 1.40(9H, s), 1.44-1.52(2H,m), 2.30(2H, br), 2.66(2H, t, J=7.3 Hz), 4.14-4.22(4H, m), 5.91(1H, br), 7.27(2H, d, J=8.3 Hz), 7.56(2H, d, J=8.3 Hz), 7.59(1H, t, J=8.3 Hz),7.69(1H, d, J=8.3 Hz), 7.78(1H, d, J=8.3 Hz), 7.95(1H, s).

Example 74 Ethyl2-t-butoxycarbonylamino-2-ethoxycarbonyl-5-[4-(3-trifluoromethyl-5-methylphenylsulfinyl)]phenylpentanoate

In a similar manner to Example 73, the compound of Example 64 was usedto obtain the desired product as a colorless oil.

FABMS:600 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.18-1.22(6H, m), 1.41(9H, s), 1.46-1.50(2H,m), 2.31(2H, br), 2.45(3H, s), 2.66(2H, t, J=7.3 Hz), 4.14-4.22(4H, m),5.92(1H, br s), 7.27(2H, d, J=7.8 Hz), 7.48(1H, s), 7.55(2H, d, J=7.8Hz), 7.62(1H, s), 7.70(1H, s).

Example 75 Alternative process for synthesizing the compound of Example9 Ethyl5-[4-(3,5-bistrifluoromethylphenoxy)phenyl]-2-t-butoxycarbonylamino-2-ethoxycarbonylpentanoate

In a similar manner to Reference Example 123, the compound of Example 69was reduced and, then, in a similar manner to Example 71, the resultingphenol was reacted with 3,5-bis(trifluoromethyl)phenylboric acid to givethe desired product as a pale yellow oil.

¹H-NMR(400 MHz, CDCl₃) δ 1.24(6H, t, J=7.3 Hz), 1.43(9H, s),1.47-1.58(4H, m), 2.36(2H, br s), 2.66(2H, t, J=7.3 Hz), 4.18-4.26(4H,m), 5.96(1H, br s), 6.96(2H, d, J=8.3 Hz), 7.20(2H, d, J=8.3 Hz),7.36(2H, s), 7.55(1H, s).

Examples 76 and 772-t-butoxycarbonylamino-2-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]propyl-1,3-propanediol(Example 76);

and2-t-butoxycarbonylamino-5-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]pentane-1-ol(Example 77)

The compound of Example 1 (1.87 g) was dissolved in THF (30 mL). Whilethis solution was stirred at 0° C., lithium borohydride (675 mg) wasadded. Ethanol (5 mL) was added and the mixture was allowed to graduallywarm to room temperature while being stirred overnight. Subsequently,ice water was added to the mixture and the organic solvent was removedunder reduced pressure. A 10% aqueous citric acid was added to theresidue to adjust the pH to 3, followed by extraction with ethylacetate. The extract was washed sequentially with water and a saturatedaqueous solution of sodium chloride. The organic phase was then driedover anhydrous sodium sulfate and the solvent was removed under reducedpressure. The residue was purified on a silica gel column chromatography(hexane:ethyl acetate=1:1) to give-the diol (1.10 g) or the monool (0.27g), each as a colorless oil.

Compound of Example 76

FABMS:520([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ1.43(9H, s), 1.62-1.65(4H, m), 2.72(2H,br),3.31(2H, br), 3.57-3.62(2H, m), 3.81-3.85(2H, m), 4.93(1H, s),7.20-7.27(3H, m), 7.38-7.55(4H, m).

Compound of Example 77

FABMS:490([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.44(9H, s), 1.63-1.73(4H, m), 2.72-2.78(2H,m), 3.57(1H, br), 3.68-3.70(2H, m), 4.61(1H, br s), 7.20-7.22(2H, m),7.39-7.55(5H, m).

Examples 78 through 184

In a similar manner to Example 76, the compounds of 2 through 68 and 70through 74 were used to synthesize compounds shown in Tables 8 through10 below. TABLE 8

Yield Examples R1 R2 R3 R4 RS X n Characteristics (%) 78 Cl c-Cl H ClCH₂OH O 3 Colorless oil 79 79 Cl c-Cl H Cl H O 3 Colorless oil 12 80t-Bu H H H CH₂OH O 3 Colorless oil 78 81 t-Bu H H H H O 3 Colorless oil15 82 CF₃ H H H CH₂OH O 3 Colorless oil 74 83 CF₃ H H H H O 3 Colorlessoil 17 84 CF₃ H OMe H CH₂OH O 3 Colorless oil 76 85 CF₃ H OMe H H O 3Colorless oil 5 86 CF₃ H H OMe CH₂OH O 3 Colorless oil 45 87 CF₃ H H OMeH O 3 Colorless oil 17 88 CF₃ H CF₃ H CH₂OH O 3 Colorless oil 68 89 CF₃H CF₃ H H O 3 Colorless oil 16 90 CF₃ H H CF₃ CH₂OH O 3 Colorless oil 4191 CF₃ H H CF₃ H O 3 Colorless oil 22 92 CF₃ c-CF₃ H H CH₂OH O 3Colorless oil 72 93 CF₃ c-CF₃ H H H O 3 Yellow oil 14 94 CF₃ c-CF₃ H ClCH₂OH O 3 Colorless oil 77 95 CF₃ c-CF₃ H Cl H O 3 Colorless oil 19 96CF₃ b-Cl H H CH₂OH O 3 Colorless powder 62 97 CF₃ b-Cl H H H O 3Colorless powder 29 98 CF₃ c-PhCH₂O H Cl CH₂OH O 3 Colorless oil 67 99CF₃ c-PhCH₂O H Cl H O 3 Colorless oil 12 100 Ph(CH₂)₂ H H Cl CH₂OH O 3Colorless oil 84 101 Ph(CH₂)₂ H H Cl H O 3 Colorless oil 15 102 Ph(CH₂)₂H H CF₃ CH₂OH O 3 Colorless oil 72 103 Ph(CH₂)₂ H H CF₃ H O 3 Colorlessoil 18 104 Ph(CH₂)₂ c-CF₃ H H CH₂OH O 3 Colorless oil 80 105 Ph(CH₂)₂c-CF₃ H H H O 3 Colorless oil 16 106 Ph(Ch₂)₂ c-Ph(CH₂)₂ H H CH₂OH O 3Colorless oil 71 107 Ph(CH₂)₂ c-Ph(CH₂)₂ H H H O 3 Colorless oil 11 108PH(CH₂)₂ c-Ph(CH₂)₂ H CF₃ CH₂OH O 3 Colorless oil 54 109 Ph(CH₂)₂c-Ph(CH₂)₂ H CF₃ H O 3 Colorless oil 13 110 Ph(CH₂)₂ c-Ph(CH₂)₂ H ClCH₂OH O 3 Colorless oil 61 111 Ph(CH₂)₂ c-Ph(CH₂)₂ H Cl H O 3 Colorlessoil 10 112 i-PrO c-iPr H Cl CH₂OH O 3 Colorless oil 82 113 i-PrO c-iPr HCl H O 3 Colorless oil 7 114 PhO H H Cl CH₂OH O 3 Colorless oil 76 115PhO H H Cl H O 3 Colorless oil 17 116 PhCH₂O H H H CH₂OH O 3 Colorlessoil 76 117 PhCH₂O H H H H O 3 Colorless oil 11 118 PhCH₂O H H Br CH₂OH O3 Colorless oil 61 119 PhCH₂O H H Br H O 3 Colorless oil 11 120 PhCH₂O HH SMe CH₂OH O 3 Colorless oil (38) 121 PhCH₂O H H SMe H O 3 Colorlessoil (10)Numbers in parentheses are cumulative yields from the previous step.

TABLE 9 Yield Examples R1 R2 R3 R4 R5 X n Characteristics (%) 122 PhCH₂OH H Me CH₂OH O 3 Colorless oil 75 123 PhCH₂O H H Me H O 3 Colorless oil11 124 PhCH₂O H H Et CH₂OH O 3 Colorless oil 61 125 PhCH₂O H H Et H O 3Colorless oil  8 126 PhCH₂O H H Cl CH₂OH S 2 Colorless powder 41 127PhCH₂O H H Cl H S 2 Pale yellow oil 11 128 PhCH₂O H H Cl CH₂OH S 3Colorless powder 65 129 PhCH₂O H H Cl H S 3 Colorless oil 26 130 PhCH₂OH H Cl CH₂OH S 4 Colorless oil 76 131 PhCH₂O H H Cl H S 4 Colorless oil15 132 PhCH₂O c-CF₃ H H CH₂OH O 3 Colorless oil 83 133 PhCH₂O c-CF₃ H HH O 3 Colorless oil 10 134 Cl H H H CH₂OH S 3 Colorless oil 41 135 Cl HH H H S 3 Colorless oil 31 136 CF₃ c-CF₃ H Cl CH₂OH S 3 Colorlessamorphous 66 137 CF₃ c-CF₃ H Cl H S 3 Colorless oil 13 138 Et H H HCH₂OH O 3 Colorless oil 76 139 Et H H H H O 3 Colorless oil 13 140 SOMeH H H CH₂OH O 3 Colorless oil 67 141 SOMe H H H H O 3 Colorless oil 27142 Cl c-Cl H H CH₂OH O 1 Colorless amorphous 56 143 Cl c-Cl H H H O 1Colorless powder 24 144 CF₃ H H PhCH₂O CH₂OH O 3 Colorless oil 64 145CF₃ H H PhCH₂O H O 3 Colorless oil  5 146 PhCH₂O H H Cl CH₂OH O 3Colorless oil 77 147 PhCH₂O H H Cl H O 3 Colorless oil 19 148 CF₃ H Cl HCH₂OH O 3 Colorless oil 58 149 CF₃ H H Cl CH₂OH O 3 Colorless oil 68 150PhCH₂O H H F CH₂OH O 3 Colorless oil 34 151 CF₃ a-Cl H H CH₂OH O 3Colorless oil 57 152 CF₃ c-Cl H H CH₂OH O 3 Colorless oil 51 153 CF₃d-Cl H H CH₂OH O 3 Colorless oil 37 154 Ph(CH₂)₂ c-CF₃ H Cl CH₂OH O 3Colorless oil 46 155 PhCH₂O H H Cl CH₂OH O 2 Colorless powder (49) 156PhCH₂O H H Cl CH₂OH O 4 Colorless oil (72) 157 CF₃ H H F CH₂OH O 3Colorless oil 63 158 PhCH₂O c-PhCH₂O H H CH₂OH O 3 Colorless oil (45)159 PhCH₂O c-PhCH₂O H Cl CH₂OH O 3 Colorless oil (17) 160 PhCH₂O c-Cl HCl CH₂OH O 3 Colorless oil 61 161 PhCH₂O H H CF₃ CH₂OH O 3 Colorless oil83 162 PhCH₂O H H Ph CH₂OH O 3 Colorless oil (50) 163 MeS H H H CH₂OH O3 Colorless powder 56 164 n-C₅H₁₁ H H H CH₂OH O 3 Colorless oil 98 165c-C₇H₁₈ H H H CH₂OH O 3 Colorless oil 90 166 iPr c-iPrO H H CH₂OH O 3Colorless oil 72 167 iPr c-iPr H Cl CH₂OH O 3 Colorless oil 33 168PhCH₂S H H H CH₂OH O 3 Colorless oil (20)Numbers in parentheses are cumulative yields from the previous step.

TABLE 10 Yield Examples R1 R2 R3 R4 R5 X n Characteristics (%) 169PhCH₂S H H Cl CH₂OH O 3 Colorless oil (11) 170 i-Bu H H H CH₂OH O 3Colorless oil 92 171 PhOCH₂ H H H CH₂OH O 3 Colorless oil 64 172 PhCH₂OH H i-Pr CH₂OH O 3 Colorless oil (62) 173 CF₃ H H H CH₂OH S 3 Colorlesspowder 89 174 CF₃ H H H CH₂OH SO 3 Colorless amorphous 71 175 CF₃ H HCF₃ CH₂OH S 3 Colorless oil 51 176 CF₃ c-Me H H CH₂OH S 3 Colorlesspowder 81 177 CF₃ c-Me H H CH₂OH SO 3 Colorless powder 65 178 MeO H H ClCH₂OH S 3 Colorless oil 56 179 PhCH₂O H H H CH₂OH S 3 Colorless oil (45)180 PhCH₂O H H CF₃ CH₂OH S 3 Colorless oil 66 181 Cl c-Cl H H CH₂OH O 3Colorless oil 50 182 Cl c-Cl H H H O 3 Colorless oil 13 183 MeSO₂ H H HCH₂OH O 3 Colorless amorphous 78 184 i-PrO H H H CH₂OH O 3 Colorless oil68Numbers in parentheses are cumulative yields from the previous step.

Example 1855-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethylpentane-1-ol

The compound of Example 146 (720 mg) was dissolved in acetonitrile (20mL). To this solution, Ag₂O (1.85 g) and MeI (3 mL) were added and themixture was stirred for 7 days at room temperature. Subsequently, themixture was filtered through Celite and the filtrate was concentratedand purified on a silica gel column chromatography (hexane:ethylacetate=3:1). This gave the desired product as a colorless oil (310 mg).

FABMS: 556 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.43(9H, s), 1.48-1.81(4H, m), 2.68(2H, t,J=7.8 Hz), 3.33(1H, d, J=8.8 Hz), 3.36(3H, s), 3.57(1H, d, 8.8 Hz),3.65(2H, d, J=6.8 Hz), 5.03(2H, s), 5.10(1H, br s), 6.59-6.62(2H, m),6.74(1H, dd, J=8.3, 2.4 Hz), 6.84(1H, dd, J=8.3, 2.4 Hz), 7.00(1H, d,J=2.4 Hz), 7.15(1H, d, J=8.3 Hz), 7.23(1H, t, J=8.3 Hz), 7.33-7.42(5H,m).

Example 1862-t-butoxycarbonylamino-2-methoxymethyl-5-[4-(3-trifluoromethylphenoxy)phenyl]pentane-1-ol

In a similar manner to Example 185, the compound of Example 82 wasreacted to obtain the desired product as a colorless oil.

FABMS: 484 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.42(9H, s), 1.48-1.83(4H, m), 2.57-2.65(2H,m), 3.33(1H, d, J=8.8 Hz), 3.37(3H, s), 3.58(1H, d, 8.8 Hz), 3.62(2H, brs), 5.07(1H, br s), 6.94(2H, d, J=6.4 Hz), 7.10-7.21(4H, m),7.30(1H, d,J=7.8 Hz), 7.40(1H, t, J=7.8 Hz).

Example 1874-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-4-hydroxymethyl-2-oxazolidinone

The compound of Example 128 (3.30 g) was dissolved in THF (80 mL). Whilethis solution was kept at 0° C., 60% sodium hydride (600 mg) was addedand the mixture was stirred for 24 hours at room temperature.Subsequently, ice water was added and the mixture was extracted withethyl acetate. The extract was washed sequentially with water and asaturated aqueous solution of sodium chloride. The organic phase wasthen dried over anhydrous sodium sulfate. The solvent was removed bydistillation and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=1:1 then 100% ethyl acetate) togive the desired product as a pale yellow oil (2.37 g).

¹H-NMR(400 MHz, CDCl₃) δ 1.63-1.72(4H, m), 2.74(2H, t, J=6.8 Hz),3.51(1H, d, J=11.2 Hz), 3.58(1H, d, J=11.2 Hz), 4.09(1H, d, J=8.8 Hz),4.24(1H, d, J=8.8 Hz), 5.02(2H, s), 5.28(1H, br s), 6.87-6.90(1H, m),6.94-7.00(2H, m), 7.09-7.16(2H, m), 7.22-7.52(7H, m).

Example 1884-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-4-iodomethyl-2-oxazolidinone

The compound of Example 187 (2.37 g) was dissolved in pyridine (30 mL).To this solution, p-toluenesulfonylchloride (1.33 g) was added and themixture was stirred for 24 hours at room temperature and a further 5hours at 60° C. Following addition of water, the mixture was extractedwith ethyl acetate. The extract was then washed sequentially with water,diluted hydrochloric acid and a saturated aqueous solution of sodiumchloride. The organic phase was dried over anhydrous sodium sulfate. Thesolvent was removed by distillation and the residue was purified on asilica gel chlomatography (hexane:ethyl acetate=1:1) to obtain asulfonic acid ester as a colorless oil (2.14 g). The sulfonic acid ester(2.14 g) was dissolved in acetone (20 mL), followed by addition ofsodium iodide (2.55 g) and refluxing for 10 hours. Subsequently, waterwas added and the mixture was extracted with ethyl acetate. The extractwas washed sequentially with water and a saturated aqueous solution ofsodium chloride. The organic phase was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation and the residue waspurified on a silica gel chlomatography (hexane:ethyl acetate=1:1) togive the desired product as a colorless oil (1.47 g).

¹H-NMR(400 MHz, CDCl₃) δ 1.59-1.65(2H, m), 1.83-1.89(2H, m), 2.75(2H, t,J=7.8 Hz), 3.31(2H, s), 4.19(1H, d, J=9.3 Hz), 4.21(1H, d, J=9.3 Hz),5.02(2H, s), 5.13(1H, br s), 6.88(1H, dd, J=7.8, 2.0 Hz), 6.94-7.00(2H,m), 7.11(1H, d, J=7.8 Hz), 7.16(1H, dd, J=7.8, 2.0 Hz), 7.22-7.41(7H,m).

Example 1894-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-4-methylthiomethyl-2-oxazolidinone

The compound of Example 188 (1.47 g) was dissolved in THF (30 mL). Tothis solution, NaSMe (210 mg) was added and the mixture was stirred for2 hours at room temperature. Following addition of water, the mixturewas extracted with ethyl acetate. The extract was then washed with asaturated aqueous solution of sodium chloride and the organic phase wasdried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure to give the desired product as a colorless oil (1.27g).

FABMS: 514 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.62-1.77(4H, m), 2.17(3H, s), 2.68(1H, d,J=13.2 Hz), 2.74(2H, t, J=7.3 Hz), 2.78(1H, d, J=13.2 Hz), 4.15(1H, d,J=9.0 Hz), 4.20(1H, d, J=9.0 Hz), 5.03(2H, s), 5.22(1H, br s),6.87-6.90(1H, m), 6.93-6.97(2H, m), 7.10-7.17(2H, m), 7.22-7.41(7H, m).

Example 1905-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methylthiomethylpentane-1-ol

The compound of Example 189 (1.27 g) was dissolved in acetonitrile (20mL). To this solution, Boc₂O (1.09 g) and dimethylaminopyridine (100 mg)were added and the mixture was stirred for 30 min at room temperature.The solvent was removed under reduced pressure and the residue waspurified on a silica gel chlomatography (hexane:ethyl acetate=4:1) toobtain an N-Boc-oxazolidinone as a colorless oil (1.48 g). This productwas dissolved in methanol (20 mL), followed by addition of cesiumcarbonate (410 mg) and stirring overnight at room temperature.Subsequently, the solvent was removed by distillation and the residuewas dissolved in ethyl acetate. The mixture was then washed sequentiallywith diluted hydrochloric acid and water and the organic phase was driedover anhydrous sodium sulfate. The solvent was removed by distillationand the residue was purified on a silica gel chlomatography(hexane:ethyl acetate=2:1) to give the desired product as a colorlessoil (1.28 g).

FABMS: 588 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.43(9H, s), 1.51-1.66(3H, m), 1.82-1.85(1H,m), 2.15(3H, s), 2.69(2H, t, J=7.3 Hz), 2.75(1H, d, J=13.4 Hz), 2.90(1H,d, J=13.4 Hz), 3.69-3.70(2H, m), 4.02(1H, br), 4.99(1H, br s), 5.02(2H,s), 6.86-6.94(3H, m), 7.12-7.17(2H, m), 7.21-7.41(7H, m).

Example 1915-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-t-butyldiphenylsiloxymethylpentane-1-ol

The compound of Example 146 (3.25 g) was dissolved in DMF (18 mL). Tothis solution, diisopropylethylamine (10.5 mL) and t-BuPh₂SiCl (1.73 g)were added and the mixture was stirred for 8 hours at room temperature.Subsequently, ice water was added and the mixture was extracted withethyl acetate. The extract was washed sequentially with water, dilutedhydrochloric acid, water and a saturated aqueous solution of sodiumchloride. The organic phase was then dried over anhydrous sodiumsulfate. The solvent was removed by distillation and the residue waspurified on a silica gel column chromatography (hexane:ethylacetate=7:1) to give the desired product as a colorless oil (1.64 g).

¹H-NMR(400 MHz, CDCl₃)5 1.06(9H, s), 1.43(9H, s), 1.49-1.82(4H, m),2.66(2H, t, J=7.8 Hz), 3.54(1H, d, J=10.3 Hz), 3.65-3.67(2H, m),3.74(1H, d, J=10.3 Hz), 5.03(2H, s), 5.05(1H, br s), 6.59(1H, dd, J=8.3,2.4 Hz), 6.63(1H, t, J=2.4 Hz), 6.74(1H, dd, J=8.3, 2.4 Hz), 6.82(1H,dd, J=8.3, 2.4 Hz), 6.99(1H, d, J=2.4 Hz), 7.10(1H, d, J=8.3 Hz),7.23(1H, t, J=8.3 Hz), 7.31-7.45(11H, m), 7.61-7.64(4H, m).

Example 1925-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-t-butyldiphenylsiloxymethylpentanal

The compound of Example 191 (940 mg) was dissolved in DMF (10 mL). Tothis solution, pyridinium dichromate (800 mg) was added and the mixturewas stirred for 48 hours at room temperature. Following addition ofwater, the mixture was extracted with ethyl acetate. The extract wasthen washed sequentially with water and a saturated aqueous solution ofsodium chloride. The organic phase was dried over anhydrous sodiumsulfate. The solvent was concentrated and the residue was purified on asilica gel chlomatography (hexane:ethyl acetate=3:1) to give the desiredproduct as a colorless oil (710 mg).

¹H-NMR(400 MHz, CDCl₃)δ 1.01 (9H, s), 1.44(9H, s), 1.49-1.73(4H, m),2.64(2H, br s), 3.84(1H, d, J=10.3 Hz), 4.13(1H, d, J=10.3 Hz), 5.03(2H,s), 5.43(1H, br s), 6.58(1H, dd, J=8.3, 2.4 Hz), 6.62(1H, t, J=2.4 Hz),6.74(1H, dd, J=8.3, 2.4 Hz), 6.82(1H, dd, J=8.3, 2.4 Hz), 6.99(1H, d,J=2.4 Hz), 7.08(1H, d, J=8.3 Hz), 7.23(1H, t, J=8.3 Hz), 7.30-7.43(11H,m), 7.56-7.64(4H, m), 9.36(1H, s).

Example 1935-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylaminopentanal

To an oxalyl chloride solution (1.0 mL) of methylene chloride (20 mL), amixture of DMSO (1.7 mL) and methylene chloride (10 mL) was added whilethe mixtures were kept at −78° C. The compound of Example 129 (5.59 g)in methylene chloride (20 mL) was then added dropwise. After 15 min,triethylamine (7.2 mL) was added and the mixture was stirred for 2 hoursuntil room temperature. Following addition of water, the mixture wasextracted with ethyl acetate and the organic phase was dried overanhydrous sodium sulfate. The solvent was then concentrated and theresidue was purified on a silica gel chlomatography (hexane:ethylacetate=3:1) to give the desired product as a pale yellow oil (4.75 g).

¹H-NMR(400 MHz, CDCl₃) δ 1.44(9H, s), 1.60-1.74(3H, m), 1.96(1H, br),2.72-2.77(2H, m), 4.28(1H, br), 5.02(2H, s), 6.87-6.95(3H, m),7.10-7.16(2H, m), 7.23(1H, t, J=7.8 Hz), 7.28-7.52(5H, m), 9.58(1H, s).

Example 194 Ethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-methylpentanoate

Sodium hydride (242 mg) was dissolved in DMF (5 mL). To this solution,diethyl methylmalonate (0.956 mL) was added and the mixture was stirredfor 30 min. The compound of Reference Example 252 (2.50 g) in DMF (5 mL)was then added and the mixture was further stirred for 1 hour.Subsequently, the reaction mixture was diluted with water and wasextracted with ethyl acetate. The ethyl acetate layer was washed with asaturated aqueous solution of sodium chloride and was dried overanhydrous sodium sulfate. The dried organic phase was concentrated andthe resulting residue was purified on a silica gel chlomatography(hexane:ethyl acetate=20:1 to 10:1) to give the desired product as ayellow oil (2.74 g).

MS (EI): 540 ( [M]⁺).

¹H-NMR(400MHz, CDCl₃) δ 1.23(6H, t, J=7.3 Hz), 1.40(3H, s), 1.52-1.60(2H, m), 1.91-1.95(2H, m), 2.70(2H, t, J=7.9 Hz), 4.16(4H, q, J=7.3 Hz),5.02(2H, s), 6.86-6.94(3H, m), 7.11-7.14(2H, m), 7.20-7.24(1H, m),7.31-7.40(6H, m).

Example 195 Ethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-ethylpentanoate

Using diethyl ethylmalonate, the reaction was carried out in the samemanner as in Reference Example 194 to give the desired product as ayellow oil.

MS(EI): 554 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.80(3H, t, J=7.3 Hz), 1.22(6H, t, J=7.3 Hz),1.45-1.53(2H, m), 1.89-1.97(4H, m), 2.70(2H, t, J=7.3 Hz), 4.16(4H, q,J=7.3 Hz), 5.02(2H, s), 6.86-6.94(3H, m), 7.11-7.16(2H, m),7.20-7.24(1H, m), 7.31-7.40(6H, m).

Example 196 Ethyl4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-methylbutyrate

Using the compound of Reference Example 317, the reaction was carriedout in the same manner as in Example 194 to give the desired product asa pale yellow oil.

MS(EI): 526 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.27(6H, t, J=7.3 Hz), 1.52(3H, s),2.10-2.14(2H, m), 2.65-2.69(2H, m), 4.20(4H, q, J=7.3 Hz), 5.02(2H, s),6.86-6.96(3H, m), 7.15(2H, s), 7.23(1H, t, J=8.0), 7.31-7.41(6H, m).

Example 197 Ethyl4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-ethylbutyrate

Using the compound of Reference Example 317, the reaction was carriedout in the same manner as in Example 195 to give the desired product asa colorless oil.

MS(EI): 540 ( [M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.82(3H, t, J=7.3 Hz), 1.17(6H, t, J=7.3 Hz),1.93(2H, q, J=7.3 Hz), 1.98-2.02(2H, m), 2.45-2.51(2H, m), 4.13(4H, q,J=7.3 Hz), 5.10(2H, s), 6.92-7.01(3H, m), 7.21(1H, dd, J=8.0, 1.9 Hz),7.30-7.41(8H, m).

Example 1985-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-methylpentanoicacid

The compound of Example 194 (2.74 g) was dissolved in ethanol (10 mL).To this solution, potassium hydroxide (330 mg) was added and the mixturewas stirred overnight at 50° C. Subsequently, the reaction mixture wasdiluted with water, followed by addition of 2 mol/L hydrochloric acidand extraction with ethyl acetate. The ethyl acetate layer was washedwith a saturated aqueous solution of sodium chloride, was dried overanhydrous magnesium sulfate, and was then concentrated. The resultingresidue was purified on a silica gel chlomatography (hexane:ethylacetate=10:1 to 2:1) to give the desired product as a yellow oil (2.38g).

MS(EI): 512 ([M]⁺).

¹H-NMR(400MHz, CDCl₃) δ 1.26(3H, t, J=7.3 Hz), 1.47(3H, s),1.53-1.62(2H, m), 1.92-2.03(2H, m), 2.71(2H, t, J=7.9 Hz), 4.22(2H, q,J=7.3 Hz), 5.02(2H, s), 6.87-6.94(3H, m), 7.10-7.14(2H, m),7.21-7.25(1H, m), 7.31-7.40(6H, m).

Example 1995-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-ethylpentanoicacid

Using the compound of Example 195, the reaction was carried out in thesame manner as in Example 198 to give the desired product as a yellowoil.

MS(EI): 526 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.84(3H, t, J=7.3 Hz), 1.28(3H, t, J=7.3 Hz),1.42-1.59(2H, m), 1.85-1.95(2H, m), 2.00-2.13(2H, m), 2.66-2.70(2H, m),4.23-4.31(2H, m), 5.02(2H, s), 6.86-6.94(3H, m), 7.08-7.15(2H, m),7.21-7.25(1H, m) , 7.30-7.40(6H, m).

Example 2004-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-methylbutyricacid

Using the compound of Example 196, the reaction was carried out in thesame manner as in Example 198 to give the desired product as a paleyellow oil.

MS(EI): 499 ( [M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.30(3H, t, J=7.3 Hz), 1.57(3H, s),2.11-2.19(2H, m), 2.69(2H, t, J=8.5 Hz), 4.24(2H, q, J=7.3 Hz), 5.02(2H,s), 6.87-6.96(3H, m), 7.14(2H, s), 7.23(1H, t, J=8.0 Hz), 7.31-7.40(6H,m).

Example 2014-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-ethylbutyricacid

Using the compound of Example 197, the reaction was carried out in thesame manner as in Example 198 to give the desired product as a paleyellow oil.

¹H-NMR(400 MHz, CDCl₃) δ 0.90(3H, t, J=7.3 Hz), 1.33(3H, t, J=7.3 Hz),1.94-1.99(1H, m), 2.05-2.12(1H, m), 2.19-2.24(2H, m), 2.59-2.64(2H, m),4.20-4.31(2H, m), 5.02(2H, s), 6.87-6.94(3H, m), 7.09-7.14(2H, m),7.23(1H, t, J=8.0 Hz), 7.29-7.40(6H, m).

Example 202 Ethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methoxycarbonylamino-2-methylpentanoate

The compound of Example 198 (2.38 g) was dissolved in benzene (20 mL).To this solution, triethylamine (0.711 mL) and DPPA (1.10 mL) wereadded. The mixture was then stirred for 10 min at room temperature andfor a further 1 hour and 30 min while being refluxed. Subsequently,methanol (3.76 mL) was added over 30 min and the mixture was stirredovernight. The reaction mixture was diluted with water and was extractedwith ethyl acetate. The ethyl acetate layer was washed with a saturatedaqueous solution of sodium chloride and was dried over anhydrousmagnesium sulfate. The dried organic phase was concentrated and theresulting residue was purified on a silica gel chlomatography(hexane:ethyl acetate=20:1 to 10:1) to give the desired product as ayellow oil (2.04 g).

MS(EI): 541 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.24(3H, t, J=7.3 Hz), 1.36-1.40(1H, m),1.54(3H, s), 1.56-1.65(1H, m), 1.80-1.87(1H, m), 2.28(1H, m),2.65-2.69(2H, m), 3.63(3H, s), 4.15-4.22(2H, m), 5.02(2H, s), 5.61(1H,br s), 6.86-6.94(3H, m), 7.09-7.15(2H, m), 7.20-7.24(1H, m),7.31-7.40(6H, m).

Example 203 Ethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-2-methoxycarbonylaminopentanoate

Using the compound of Example 199, the reaction was carried out in thesame manner as in Example 202 to obtain the desired product as a yellowoil.

MS(EI): 555 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.74(3H, t, J=7.3 Hz), 1.24(3H, t, J=7.3 Hz),1.28-1.32(1H, m), 1.57-1.58(1H, m), 1.70-1.84(2H, m), 2.34-2.44(2H, m),2.62-2.72(2H, m), 3.63(3H, s), 4.16-4.22(2H, m), 5.02(2H, s), 5.78(1H,br s), 6.86-6.94(3H, m), 7.08-7.15(2H, m), 7.20-7.24(1H, m),7.31-7.40(6H, m).

Example 204 Ethyl4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methylbutyrate

Using the compound of Example 200 and t-butanol instead of methanol, thereaction was carried out in the same manner as in Example 202 to obtainthe desired product as a pale yellow oil.

FABMS: 569([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.29(3H, t, J=7.3 Hz), 1.46(9H, s), 1.58(3H,s), 2.10(1H, td, J=13.0, 4.9 Hz), 2.41(1H, br), 2.53(1H, td, J=13.0, 4.9Hz), 2.67(1H, td, J=13.0, 4.9 Hz), 4.19(2H, q, J=7.3 Hz), 5.02(2H, s),5.46(1H, br s), 6.86-6.94(3H, m), 7.08-7.15(2H, m), 7.23(1H, t, J=8.0Hz), 7.30-7.40(6H, m).

Example 205 Ethyl4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-2-methoxycarbonylaminobutyrate

Using the compound of Example 201, the reaction was carried out in thesame manner as in Example 202 to obtain the desired product as a paleyellow oil.

MS(EI): 541 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.77(3H, t, J=7.3 Hz), 1.30(3H, t, J=7.3 Hz),1.75-1.80(1H, m), 2.05-2.15(1H, m), 2.36-2.49(2H, m), 2.59-2.68(2H, m),3.66(3H, s), 4.11-4.27(2H, m), 5.02(2H, s), 5.87(1H, br), 6.86-6.93(3H,m), 7.08-7.14(2H, m), 7.22(1H, t, J=8.0 Hz), 7.30-7.40(6H, m).

Example 2065-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methoxycarbonylamino-2-methylpentane-1-ol

Using the compound of Example 202, the reaction was carried out in thesame manner as in Example 76 to obtain the desired product as acolorless oil.

MS(EI): 499 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.18(3H, s), 1.57-1.84(4H, m), 2.71(2H, t,J=7.3 Hz), 3.59-3.69(3H, m), 3.63(3H, s), 4.71(1H, br s), 5.02(2H, s),6.86-6.94(3H, m), 7.13-7.17(2H, m), 7.21-7.25(1H, m), 7.30-7.41(6H, m).

Examples 207 and 208 (+) and(−)-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methoxycarbonylamino-2-methylpentane-1-ols

The compound of Example 206 was optically resolved by a high performanceliquid chromatography (HPLC) (chiralcel OD, hexane:isopropanol=70:30,detection wavelength=UV 254 nm, flow rate=3 mL/min).

The compound obtained from the first eluate had an optical rotation[α]^(24.0) _(D) of +15° (C=1.0, chloroform) (Example 207), while thecompound obtained from the second eluate had an optical rotation[α]^(24.7) _(D) of −12° (C=1.0, chloroform) (Example 208).

Example 2095-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-2-methoxycarbonylaminopentane-1-ol

Using the compound of Example 203, the reaction was carried out in thesame manner as in Example 76 to obtain the desired compound as a paleyellow oil.

MS(EI): 513 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.83(3H, t, J=7.3 Hz), 1.51-1.73(6H, m), 2.70(2H, t, J=7.3 Hz), 3.63(3H, s), 3.65-3.70(3H, m), 4.63(1H, br s),5.02(2H, s), 6.86-6.94(3H, m), 7.12-7.17(2H, m), 7.20-7.24(1H, m),7.30-7.40(6H, m).

Examples 210 and 211 (+) and(−)-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-2-methoxycarbonylaminopentane-1-ols

The compound of Example 209 was optically resolved by HPLC (chiralcelOD, hexane:isopropanol=60:40, detection wavelength=UV 254 nm, flowrate=3 mL/min).

The colorless oil obtained from the first eluate had an optical rotation[α]^(25.6) _(D) of +14° (C=1.0, chloroform) (Example 210), while thecolorless oil obtained from the second eluate had an optical rotation[α]^(25.7) _(D) of −15° (C=1.0, chloroform) (Example 211).

Example 2124-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methylbutane-1-ol

Using the compound of Example 204, the reaction was carried out in thesame manner as in Example 76 to obtain the desired compound as acolorless oil.

MS(EI): 527 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.25(3H, s), 1.44(9H, s), 1.82(1H, td, J=13.0,4.9 Hz), 2.06(1H, td, J=13.0, 4.9 Hz), 2.65-2.80(2H, m), 3.66-3.74(2H,m), 4.68(1H, br s), 5.02(2H, s), 6.86-6.94(3H, m), 7.15(2H, s), 7.23(1H,t, J=8.0 Hz), 7.32-7.40(6H, m).

Examples 213 and 214 (+) and(−)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methylbutane-1-ols

The compound of Example 212 was optically resolved by HPLC (chiralpakAD, hexane:isopropanol=85:15, detection wavelength=UV 254 nm, flowrate=3 mL/min).

The colorless oil obtained from the first eluate had an optical rotation[α]^(25.3) _(D) of +4.6° (C=1.0, chloroform) (Example 213), while thecolorless oil obtained from the second eluate had an optical rotation[α]^(25.6) _(D) of −2.2° (C=1.0, chloroform) (Example 214).

Example 2154-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-2-methoxycarbonylaminobutane-1-ol

Using the compound of Example 205, the reaction was carried out in thesame manner as in Example 76 to obtain the desired product as acolorless oil.

MS(EI): 499 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.94(3H, t, J=7.3 Hz), 1.69(2H, q, J=7.3 Hz),1.80-1.94(2H, m), 2.62-2.75(2H, m), 3.65(3H, s), 3.77(3H, m), 4.77(1H,br), 5.02(2H, s), 6.86-6.95(3H, m), 7.16(2H, s), 7.23(1H, t, J=8.0 Hz),7.32-7.41(6H, m).

Examples 216 and 217 (+) and(−)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-2-methoxycarbonylaminobutane-1-ols

The compound of Example 215 was optically resolved under similarconditions to those used in Examples 213 and 214.

The colorless oil obtained from the first eluate had an optical rotation[α]^(25.6) _(D) of +11.1° (C=1.0, chloroform) (Example 216), while thecolorless oil obtained from the second eluate had an optical rotation[α]^(26.1) _(D) of −9.67° (C=1.0, chloroform) (Example 217).

Example 2185-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-butoxycarbonylamino-2-ethylpentane-1-ol

Using the compound of Example 199 and t-butanol instead of methanol, thesame procedure was followed as in Example 203 and the reactant wasreduced in the same manner as in Example 76 to obtain the desiredproduct as a colorless oil.

MS (EI): 555 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.83(3H, t, J=7.3 Hz), 1.42(9H, s),1.55-1.72(6H, m), 2.70(2H, t, J=6.7 Hz), 3.64-3.66(2H, m), 4.49(1H, brs), 5.02(2H, s), 6.82-6.95(3H, m), 7.12-7.17(2H, m), 7.20-7.25(1H, m),7.30-7.41(6H, m).

Example 2194-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethyloxymethylbutnane-1-ol

The compound of Example 126 (4.00 g) was dissolved in methylene chloride(100 mL). To this solution, diisopropylethylamine (1.54 mL) was added,followed by dropwise addition of methoxymethylchloride (710 mg) at 0° C.The mixture was stirred for one day until room temperature. Followingaddition of ice water, the mixture was extracted with ethyl acetate. Theextract was then dried over anhydrous sodium sulfate and the solvent wasremoved by distillation. The resulting residue was purified on a silicagel chlomatography (hexane:ethyl acetate=2:1) to give the desiredproduct as a colorless oil (2.60 g).

¹H-NMR(400 MHz, CDCl₃) δ 1.45(9H, s), 1.90-2.00(2H, m), 2.68-2.78(2H,m), 3.39(3H, s), 3.54(1H, d, J=9.8 Hz), 3.77(2H, d, J=6.1 Hz), 3.79(1H,d, J=9.8 Hz), 3.99(1H, br), 4.65(2H, s), 5.02(2H, s), 5.20(1H, br s),6.86-6.94(3H, m), 7.13-7.17(2H, m), 7.22(1H, t, J=8.0 Hz), 7.31-7.40(6H,m).

Examples 220 and 221 (+) and(−)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethyloxymethylbutane-1-ols

The compound of Example 219 was optically resolved by HPLC (chiralpakAD-H, hexane:isopropanol=85:15, detection wavelength=UV 254 nm, flowrate=3 mL/min).

A colorless oil was obtained from each of the first eluate and thesecond eluate (Example 220 and Example 221, respectively).

Example 2225-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-butoxycarbonylamino-2-methoxymethyloxymethylpentane-1-ol

Using the compound of Example 128, the reaction was carried out in thesame manner as in Example 219 to obtain the desired product as acolorless oil.

¹H-NMR(400 MHz, CDCl₃) δ 1.43(9H, s), 1.56-1.68(3H, m), 1.81-1.84(1H,m), 2.67(2H, t, J=7.8 Hz), 3.35(3H, s), 3.46(1H, d, J=9.8 Hz),3.66-3.68(2H, m), 3.71(1H, d, J=9.8 Hz), 4.61(2H, s), 5.02(2H, s),5.07(1H, br s), 6.87(1H, ddd, J=8.3, 2.5, 1.0 Hz), 6.91-6.95(2H, m),7.12-7.16(2H, m), 7.23(1H, t, J=7.8 Hz), 7.31-7.40(6H, m).

Example 2234-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethyloxymethyl-1-dimethoxyphosphoryloxybutane

To a methylene chloride solution (2 mL) containing the compound ofExample 219 (860 mg), carbon tetrabromide (533 mg) and pyridine (2 mL),trimethyl phosphite (0.19 mL) was added while the mixture was stirred at0° C. and the mixture was stirred for 5 hours until room temperature.Subsequently, water was added and the mixture was extracted with ethylacetate. The extract was washed sequentially with water and a saturatedaqueous solution of sodium chloride. The organic phase was then driedover anhydrous sodium sulfate. The solvent was removed by distillationand the residue was purified on a silica gel column chromatography(hexane:ethyl acetate=1:1) to obtain the desired product as a colorlessoil (830 mg).

FABMS: 696 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.45(9H, s), 1.95-2.03(1H, m), 2.08-2.21(1H,m), 2.69-2.78(2H, m), 3.39(3H, s), 3.68(1H, d, J=9.8 Hz), 3.74(1H, d,J=9.8 Hz), 3.78(6H, d, J=11.0 Hz),4.22-4.29(2H, m), 4.65(2H, s),4.97(1H, br s), 5.02(2H, s), 6.88(1H, dd, J=7.9, 2.4 Hz), 6.91-6.95(2H,m), 7.14(2H, s), 7.23(1H, t, J=7.8 Hz), 7.31-7.40(6H, m).

Example 224(−)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethyloxymethyl-1-dimethoxyphosphoryloxybutane

Using the compound of Example 220 (first eluate), the reaction wascarried out in the same manner as in Example 223 to obtain the desiredproduct as a colorless oil.

[α]²⁶ _(D)=−3.01° (C=0.93, chloroform).

Example 225(+)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethyloxymethyl-1-dimethoxyphosphoryloxybutane

Using the compound of Example 221 (second eluate), the reaction wascarried out in the same manner as in Example 223 to obtain the desiredproduct as a colorless oil.

[α]²⁶ _(D)=+1.39° (C=1.03, chloroform).

Example 226(±)-2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentane-1-ol

The compound of Example 206 (527 mg) was dissolved in a mixed solventcomposed of a 5 mol/L aqueous solution of potassium hydroxide (2 mL),tetrahydrofuran (2 mL) and methanol (3 mL). This mixture was refluxedand stirred for 4 days. Subsequently, the reaction mixture was dilutedwith water and was extracted with ethyl acetate. The ethyl acetate layerwas then washed with a saturated aqueous solution of sodium chloride,was dried over anhydrous magnesium sulfate, and was then concentrated.The resulting residue was purified on a silica gel column chromatography(aminated silica gel, ethyl acetate:ethanol=20:1) to give the desiredproduct as a pale yellow oil (311 mg).

FABMS: 442 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.04(3H, s), 1.37-1.67(4H, m), 2.70(2H, t,J=7.3 Hz), 3.29(2H, q, J=9.2 Hz), 5.02(2H, s), 6.86-6.94(3H, m),7.12-7.17(2H, m), 7.21-7.25(1H, m), 7.31-7.41(6H, m).

Example 227(+)-2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentane-1-ol

Using the compound of Example 207 (first eluate), the reaction wascarried out in the same manner as in Example 226 to obtain the desiredproduct as a pale yellow oil. Elemental analysis(%): C₂₅H₂₈ClNO₂S.1/3H₂OC H N Calcd: 67.00 6.45 3.13 Found: 67.03 6.51 3.20[α]^(25.2) _(D) +2.0°(C = 1.0, chloroform)

Example 228(−)-2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentane-1-ol

Using the compound of Example 208 (second eluate), the reaction wascarried out in the same manner as in Example 226 to give the desiredproduct as a pale yellow oil. Elemental analysis(%): C₂₅H₂₈ClNO₂S.1/4H₂OC H N Calcd: 67.23 6.44 3.14 Found: 67.19 6.44 3.15[α]^(25.5) _(D) −2.6°(C = 1.0, chloroform)

Example 229(+)-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methylpentane

The compound of Example 227 (410 mg) was dissolved in acetonitrile (10mL). While this solution was chilled in an ice bath, Boc₂O (303 mg) wasadded and the mixture was stirred for 3 hours at room temperature. Thereaction mixture was concentrated and the residue was dissolved in ethylacetate. This solution was washed with water and a saturated aqueoussolution of sodium chloride. The organic phase was then dried overanhydrous sodium sulfate and was concentrated. The resulting residue waspurified on a silica gel column chromatography (hexane:ethylacetate=5:1) to give a t-butoxycarbonylamino product as a pale yellowoil (473 mg). The resulting compound (473 mg), along with carbontetrabromide (434 mg), was dissolved in pyridine (2.00 mL). While thissolution was chilled in an ice bath, trimethyl phosphite (0.205 mL) wasadded and the mixture was allowed to warm to room temperature and wasstirred for 2 hours. Subsequently, the reaction mixture was diluted withwater and was extracted with ethyl acetate. The extract was then washedwith a saturated aqueous solution of sodium chloride, was dried overanhydrous magnesium sulfate, and was then concentrated. The resultingresidue was purified on a silica gel column chromatography (hexane:ethylacetate=5:1 to 1:1) to give the desired product as a pale yellow oil(534 mg).

¹H-NMR(400 MHz, CDCl₃) δ 1.25(3H, s), 1.41(9H, s), 1.58-1.91(4H, m),2.70(2H, t, J=7.3 Hz), 3.77(6H, d, J=11.0 Hz), 3.96-4.00(1H, m),4.13-4.16(1H, m), 4.51(1H, brs), 5.02(2H, s), 6.86-6.89(1H, m),6.92-6.96(2H, m), 7.11-7.16(2H, m), 7.23(1H, t, J=7.9 Hz), 7.31-7.34(2H,m), 7.35-7.39(4H, m).

Example 230(−)-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methylpentane

Using the compound of Example 228, the reaction was carried out in thesame manner as in Example 229 to obtain the desired product as a paleyellow oil.

¹H-NMR(400 MHz, CDCl₃) δ 1.25(3H, s), 1.41(9H, s), 1.58-1.91(4H, m),2.70(2H, t, J=7.3 Hz), 3.77(6H, d, J=11.0 Hz), 3.97-4.00(1H, m),4.13-4.17(1H, m), 4.51(1H, brs), 5.02(2H, s), 6.86-6.89(1H, m),6.92-6.95(2H, m), 7.11-7.16(2H, m), 7.23(1H, t, J=7.9 Hz), 7.32-7.34(2H,m), 7.35-7.40(4H, m).

Example 2315-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-methoxymethyloxymethyl-1-dimethoxyphosphoryloxypentane

Using the compound of Example 222, the reaction was carried out in thesame manner as in Example 223 to obtain the desired product as acolorless oil.

FABMS: 710 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.41(9H, s), 1.57-1.62(2H, m), 1.76-1.80(1H,m), 2.00-2.05(1H, m), 2.70(2H, t, J=7.8 Hz), 3.34(3H, s), 3.57(1H, d,J=9.5 Hz), 3.65(1H, d, J=9.5 Hz), 3.77(6H, d, J=11.0 Hz), 4.12(2H, d,J=7.1 Hz), 4.60(2H, s), 4.81(1H, br s), 5.02(2H, s), 6.87(1H, ddd,J=8.3, 2.5, 1.0 Hz), 6.92-7.00(2H, m), 7.10-7.16(2H, m), 7.23(1H, t,J=7.8 Hz), 7.28-7.52(6H, m).

Example 232 Diethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-1-hexenylphosphonate

Ethyl methylenebisphosphonate (940 mg) in THF (5 mL) was chilled to −78°C. under an argon gas atmosphere. To this solution, a 1.6 mol/Ln-BuL-hexane solution (2 mL) was added dropwise and the mixture wasstirred for 30 min, followed by dropwise addition of a THF solution (15mL) of the compound of Example 193 (1.58 g). After 3 hours, a saturatedammonium chloride solution was added and the mixture was extracted withethyl acetate. The organic phase was washed with water and a saturatedaqueous solution of sodium chloride and was dried over anhydrous sodiumsulfate. The solvent was removed by distillation to give the desiredproduct as a colorless oil (1.71 g).

FABMS: 660([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.29-1.33(6H, m), 1.43(9H, s), 1.54-1.68(4H,m), 2.71-2.73(2H, m ), 4.03-4.11(4H, m), 4.32(1H, br), 4.47(1H, br),5.03(2H, s), 5.77(1H, t, J=17.7 Hz), 6.60-6.71(1H, m), 6.87-6.96(3H, m),7.09-7.15(2H, m), 7.21-7.41(7H, m).

Example 233 Diethyl3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-1-hexenylphosphonatehydrochloride

The compound of Example 232 (300 mg) was dissolved in methanol (10 mL)containing 10% hydrochloric acid in an ice bath. The mixture was stirredfor 6 hours until room temperature and the solvent was concentrated.This gave the desired product as a colorless oil (250 mg).

FABMS: 560 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.16-1.22(6H, m), 1.53-1.77(4H, m),2.68-2.69(2H, m ), 3.05(1H, br), 3.94-4.07(4H, m), 5.09(2H, s), 6.13(1H,t, J=17.8 Hz), 6.46-6.55(1H, m), 6.89-7.00(3H, m), 7.20-7.22(1H, m),7.29-7.41(8H, m), 8.44(3H, br s).

Example 234 Diethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylaminohexylphosphonate

The compound of Example 232 was reduced in the same manner as inReference Example 125 to obtain the desired product as a colorless oil.

FABMS: 662 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.32(6H, t, J=7.3 Hz), 1.43(9H, s),1.46-1.82(8H, m), 2.67-2.73(2H, m), 3.62(1H, br), 4.03-4.13(4H, m),4.32-4.34(1H, br), 5.02(2H, s), 6.86-6.95(3H, m), 7.10-7.16(2H, m),7.23(1H, t, J=8.0 Hz), 7.32-7.40(6H, m).

Example 235 Diethyl3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]hexylphosphonatehydrochloride

The compound of Example 234 was reacted in the same manner as in Example233 to obtain the desired product as a pale brown oil.

FABMS: 562 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.21(6H, t, J=6.7 Hz), 1.59-1.85(8H, m),2.67(2H, br s), 3.15(1H, br s), 3.91-4.01(4H, m), 5.08(2H, s),6.88-6.99(3H, m), 7.21-7.39(9H, m), 8.08(3H, br s).

Example 2362-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylpentylphosphonatemonoester

To an acetonitrile solution (5 mL) of the compound of Example 231 (500mg), TMSI (0.5 mL) was added and the mixture was stirred for 3 hours.The solvent was concentrated and the residue was purified on a silicagel column chromatography to obtain the desired product as a colorlesspowder (120 mg).

FABMS: 538 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.60(4H, br s), 2.63(2H, br s), 3.38-3.44(2H,m), 3.72(2H, br s), 5.08(2H, s), 6.87-6.98(3H, m), 7.20-7.38(9H, m).Elemental analysis(%): C₂₅H₂₉ClNO₆SP.H₂O C H N Calcd: 54.00 5.62 2.52Found: 54.10 5.37 2.62

Example 2372-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylbutylphosphonatemonoester

Using the compound of Example 223, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 524 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.77-1.78(2H, m), 2.71-2.75(2H, m),3.50-3.58(2H, m), 3.76-3.88(2H, m), 5.08(2H, s), 6.89(1H, t, J=7.3 Hz),6.96-6.99(2H, m), 7.21-7.38(9H, m). Elemental analysis(%): C₂₄H₂₇ClNO₆SPC H N Calcd: 55.01 5.19 2.67 Found: 54.94 5.26 2.77m.p. = 200-202° C.

Example 2382-amino-5-[2-chloro-4-(3-hydroxyphenylthio)phenyl]-2-hydroxymethylpentylphosphonatemonoester

Instead of ice-cold environment, the experiment of Example 236 wascarried out at room temperature to give the desired product as acolorless powder.

FABMS: 448 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.54-1.62(4H, m), 2.51-2.73(2H, m),3.37-3.41(2H, m), 3.57-3.75(2H, m), 6.62(1H, dd, J=8.0, 1.8 Hz),6.67-6.68(1H, m), 6.75(1H, dd, J=8.6, 1.2 Hz), 7.15(1H, t, J=8.0 Hz),7.27(1H, dd, J=8.0, 2.0 Hz), 7.34-7.36(2H, m). Elemental analysis(%):C₁₈H₂₃ClNO₆SP.0.5H₂O C H N Calcd: 47.32 5.29 3.07 Found: 47.06 5.07 3.07m.p. = 180-182° C.

Example 239(+)-2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentylphosphonatemonoester

The compound of Example 229 was reacted in the same manner as in Example236 to obtain the desired product as a colorless powder.

HR-MS(FAB+): 522.1255 (−1.6 mmu).

¹H-NMR(400 MHz, DMSOd₆) δ 1.12(3H, s), 1.51-1.65(4H, m), 2.64-2.70(2H,m), 3.66(2H, d, J=11 Hz), 5.09(2H, s), 6.91(1H, d, J=7.3 Hz),6.97-7.01(2H, m), 7.20-7.24(1H, m), 7.30-7.42(8H, m). Elementalanalysis(%): C₂₅H₂₉ClNO₅PS.1/2H₂O C H N Calcd: 56.55 5.69 2.64 Found:56.40 5.60 2.77[α]^(22.6) _(D) +3.2°(C = 1.0, methanol).m.p. = 207-210° C.

Example 240(−)-2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentylphosphonatemonoester

Using the compound of Example 228, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

HR-MS(FAB+): 522.1277 (+0.6 mmu).

¹H-NMR(400 MHz, DMSOd₆) δ 1.12(3H, s), 1.51-1.65(4H, m), 2.63-2.70(2H,m), 3.67(2H, d, J=12 Hz), 5.09(2H, s), 6.89-6.92(1H, m), 6.96-7.01(2H,m), 7.22-7.24(1H, m), 7.32-7.42(8H, m).

[α]^(23.4) _(D)−3.1° (C=1.0, methanol).

m.p.=200-203° C.

Example 2413-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]hexylphosphonic acid

Using the compound of Example 234, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 506 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.56-1.72(8H, m), 2.67(2H, br s), 3.18(1H, brs), 5.08(2H, s), 6.88-7.00(3H, m), 7.21-7.40(9H, m). Elementalanalysis(%): C₂₅H₂₉ClNO₄PS.1/2H₂O C H N Calcd: 58.30 5.87 2.72 Found:58.29 5.71 2.80

Example 2423-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-1-hexenylphosphonicacid

Using the compound of Example 232, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 504 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.53-1.70(4H, m), 2.69(2H, t, J=7.3 Hz),3.83-3.99(1H, m), 5.12(2H, s), 6.03(1H, t, J=16.5 Hz), 6.28(1H, d,d,d,J=16.5, 10.0, 7.3 Hz), 6.89-7.01(3H, m), 7.20-7.41(9H, m).

Example 2434-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-t-butyldimethylsiloxymethyl-1-dimethoxyphosphoryloxybutane

The compound of Example 126 was reacted with t-BuMe₂SiCl in the samemanner as in Example 191. The resulting compound was reacted in the samemanner as in Example 223 to give the desired product as a colorless oil.

FABMS: 766 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.09(6H, s), 0.91(9H, s), 1.45(9H, s),1.86-1.98(1H, m), 2.05-2.15(1H, m), 2.72(2H, t, J=8.6 Hz), 3.72(2H, s),3.78(6H, d, J=11.0 Hz), 4.17-4.24(2H, m), 4.78(1H, br s), 5.02(2H, s),6.86-6.95(3H, m), 7.21(2H, s), 7.23(1H, t, J=7.3 Hz), 7.31-7.41(6H, m).

Example 2444-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-hydroxymethyl-1-dimethoxyphosphoryloxybutane

To a THF solution (30 mL) of the compound of Example 243 (2.70 g), 1mol/L tetrabutylammonium fluoride in THF (5 mL) was added and themixture was stirred for 1 hour at room temperature. Following additionof water, the mixture was extracted with ethyl acetate. The extract waswashed with a saturated aqueous solution of sodium chloride and theorganic phase was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation and the residue was purified on a silica gelcolumn chromatography (hexane:ethyl acetate=2:1) to obtain the desiredproduct as a colorless oil (2.30 g).

FABMS: 652 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.45(9H, s), 1.83-1.90(1H, m), 2.09-2.17(1H,m), 2.71(2H, t, J=8.6 Hz), 3.71-3.77(2H, m), 3.79(6H, d, J=11.0 Hz),4.04(1H, br), 4.17-4.29(2H, m), 5.00(1H, br s), 5.02(2H, s),6.86-6.95(3H, m), 7.14-7.15(2H, m), 7.23(1H, t, J=7.3 Hz), 7.31-7.39(6H,m).

Examples 245 and 246 (+) and(−)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-t-butyldimethylsiloxymethyl-1-dimethoxyphosphoryloxybutanes

The compound of Example 244 was optically resolved by HPLC (chiralpakAS-H, hexane:isopropanol=8:2, detection wavelength=UV 254 nm, flowrate=1 mL/min). The colorless oil obtained from the first eluate had anoptical rotation [α]²⁶ _(D) of −6.12° (C=1.0, methanol) (Example 245),while the colorless oil obtained from the second eluate had an opticalrotation [α]²⁷ _(D) of +5.79° (C=1.0, methanol) (Example 246).

Example 247(+)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methylbutane

Using the compound of Example 213, the reaction was carried out in thesame manner as in Example 223 to obtain the desired product as a palebrown oil.

FABMS: 636 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.36(3H, s), 1.44(9H, s), 1.77-1.82(1H, m),2.05-2.15(1H, m), 2.68-2.74(2H, m), 3.78(6H, d, J=11.0 Hz),4.01-4.05(1H, m), 4.21-4.25 (1H, m), 4.63(1H, br), 5.02(2H, s),6.87-6.94(3H, m), 7.23-7.27(3H, m), 7.32-7.42(6H, m).

Example 248(−)-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-1-dimethoxyphosphoryloxy-2-methylbutane

Using the compound of Example 214, the reaction was carried out in thesame manner as in Example 223 to obtain the desired product as a palebrown oil.

FABMS: 636 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.36(3H, s), 1.44(9H, s), 1.74-1.82(1H, m),2.05-2.15(1H, m), 2.66-2.76(2H, m), 3.78(6H, d, J=11.0 Hz),4.01-4.05(1H, m), 4.21-4.25 (1H, m), 4.63(1H, br), 5.02(2H, s),6.86-6.95(3H, m), 7.21-7.27(3H, m), 7.31-7.41(6H, m).

Example 249(+)-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutylphosphonatemonoester

Using the compound of Example 247, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 508 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆-TFA) δ 1.29(3H, s), 1.72-1.84(2H, m), 2.71(2H, t,J=7.9 Hz), 3.87(1H, dd, J=4.9, 11.0 Hz), 3.93(1H, dd, J=4.9, 11.0 Hz),5.08(2H, s), 6.91(1H, d, 7.3 Hz), 6.96-7.01(2H, m), 7.23(1H, dd, J=1.8,7.9 Hz), 7.29-7.40(8H, m).

[α]^(25.6) _(D)+15.1° (C=1.0, 10% TFA in DMSO). Elemental analysis(%):C₂₄H₂₇ClNO₅PS.2/3CF₃CO₂H C H N Calcd: 52.10 4.78 2.40 Found: 52.29 4.752.68

Example 250(−)-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutylphosphonatemonoester

Using the compound of Example 248, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 508 ([M+H]⁺).

¹H-NMR(400 MHz, DMSO-TFA) δ 1.29(3H, s), 1.76-1.90(2H, m), 2.71(2H, t,J=7.9 Hz), 3.87(1H, dd, J=4.9, 11.0 Hz), 3.93(1H, dd, J=4.9, 11.0 Hz),5.08(2H, s), 6.90-7.01(3H, m), 7.24(1H, dd, J=1.8, 7.9 Hz),7.29-7.40(8H, m).

[α]^(26.3) _(D) −12.6° (C=1.0, 10% TFA in DMSO). Elemental analysis (%):C₂₄H₂₇ClNO₅PS.1/2H₂O C H N Calcd: 55.76 5.46 2.71 Found: 55.77 5.19 2.97

Examples 251 and 252 Diethyl (Z)- and(E)-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-1-fluoro-1-pentenylphosphonates

The compound of Example 127 was oxidized in the same manner as inExample 193 to obtain an aldehyde for use in the subsequent reaction.

Meanwhile, trimethylchlorosilane (1.0 mL) was added to diethyldibromofluoromethylphosphate (1.48 mL) in THF (75 mL), and the mixturewas cooled to −78° C. Subsequently, 1.6 mol/L n-butyllithium in hexane(11.3 mL) was added dropwise and the mixture was stirred for 40 min.Subsequently, the aldehyde obtained above (3.68 g) in THF (25.0 mL) wasadded dropwise over 10 min. The mixture was allowed to warm to 0° C. andwas stirred for 5 hours. Following addition of aqueous ammoniumchloride, the mixture was extracted with ethyl acetate. The ethylacetate layer was then washed with a saturated aqueous solution ofsodium chloride, was dried over anhydrous sodium sulfate, and wasconcentrated. The resulting residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=10:1 to 1:1). As a result, theZ-form was obtained from the first eluate as a yellow oil (1.70 g), andthe E-form was obtained from the second eluate as a yellow oil (667 mg).

Z-form: Example 251

FABMS: 664 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.31-1.38(6H, m), 1.43(9H, s), 1.88-2.00(2H,m), 2.69-2.83(2H, m), 4.13-4.22(4H, m), 4.80-4.90(1H, m), 5.02(2H, s),5.15-5.30(1H, br), 6.08-6.30(1H, m), 6.87-6.88(1H, m), 6.90-6.95(2H, m),7.11-7.15(2H, m), 7.22(1H, t, J=7.9 Hz), 7.31-7.39(6H, m).

E-form: Example 252

FABMS: 663 ([M]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.34-1.36(6H, m), 1.44(9H, s), 1.82-1.88(2H,m), 2.71-2.78(2H, m), 4.15-4.23(4H, m), 4.60-4.65(2H, m), 5.02(2H, s),5.80-6.00(1H, m), 6.89(1H, dd, J=1.4, 7.9 Hz), 6.93-6.95(2H, m),7.11-7.17(2H, m), 7.23(1H, t, J=7.9 Hz), 7.31-7.41(6H, m).

Example 253(Z)-3-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-1-fluoro-1-pentenylphosphonicacid

Using the compound of Example 251, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 508 ([M+H]⁺).

¹H-NMR(400 MHz, DMSd₆) δ 1.78-1.98 (2H, m), 2.69(2H, t, J=7.9 Hz),4.19(1H, br), 5.08(2H, s), 5.47-5.62(1H, m), 6.90(1H, d, J=7.9 Hz),6.97-6.99(2H, m), 7.20(1H, d, J=7.9 Hz), 7.29-7.40(8H, m), 8.67(2H, br).

m.p.=285-288° C. Elemental analysis (%): C₂₄H₂₄ClFNO₄PS.13/10H₂O C H NCalcd: 54.25 5.05 2.64 Found: 54.54 5.49 2.44

Example 254(E)-3-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-1-fluoro-1-pentenylphosphonicacid

Using the compound of Example 252, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 508 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.79-1.91(1H, m), 1.91-2.02(1H, m),2.58-2.70(2H, m), 3.84-3.98(1H, m), 5.08(2H, s), 5.43-5.62(1H, m),6.90(1H, m), 6.95-6.99(2H, m), 7.17-7.38(9H, m), 8.68(2H, br).

m.p.=288-290° C.

Examples 255 and 256 Diethyl (Z)- and(E)-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-1-fluoro-1-hexenylphosphonates

The compound of Example 193 was reacted in the same manner as inExamples 251 and 252 to obtain the desired Z-form (Example 255) and theE-form (Example 256), respectively. Each product was obtained as ayellow oil.

Z-form: Example 255

FABMS: 678 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.31-1.37(6H, m), 1.41(9H, s), 1.61-1.71(4H,m), 2.73(2H, m), 4.10-4.18(4H, m), 4.84(1H, br), 5.02(2H, s),5.06-5.15(1H, m), 6.01-6.19(1H, m), 6.87(1H, dd, J=1.2, 9.7 Hz),6.91-6.94(2H, m), 7.12-7.16(2H, m), 7.22(1H, t, J=7.9 Hz), 7.30-7.39(6H,m).

E-form: Example 256

FABMS: 678 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.32-1.37(6H, m), 1.43(9H, s), 1.61-1.66(4H,m), 2.72(2H, t, J=7.3 Hz), 4.11-4.17(4H, m), 4.50-4.60(2H, m), 5.02(2H,s), 5.73-5.90(1H, m), 6.86-6.89(1H, m), 6.92-6.96(2H, m), 7.10(1H, d,J=7.9 Hz), 7.13(1H, dd, J=1.2, 7.9 Hz), 7.23(1H, t, J=7.9 Hz),7.31-7.40(6H, m).

Example 257 Diethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-1-fluorohexylphosphonate

Using the compounds of Examples 255 and 256, the reaction was carriedout in the same manner as in Reference Example 123 to obtain the desiredproduct as a yellow oil.

FABMS: 679 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.35(6H, s), 1.43(9H, s), 1.49-1.57(2H, m),1.58-1.75(4H, m), 2.65-2.80(2H, m), 3.82-3.94(1H, m), 4.20 (4H, q, J=7.3Hz), 4.35-4.55(1H, m), 4.74-4.94(1H, m), 5.02(2H, s), 6.87-6.99(1H, m),6.92-6.95(2H, m), 7.11-7.17(2H, m), 7.23(1H, t, J=7.9 Hz), 7.32-7.43(6H,m).

Example 258 Dimethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-methyl-1-hexenylphosphonate

Following the same procedure as in Example 229, the compound of Example226 was reacted to form a Boc product and, following the same procedureas in Example 193, the product was oxidized to an aldehyde.Subsequently, using methyl methylenebisphosphonate, the same procedurewas followed as in Example 232 to give the desired product as a paleyellow oil.

FABMS: 646 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.36(3H, s), 1.40(9H, s), 1.54-1.64(2H, m),1.67-1.70(1H, m), 1.82-1.92(1H, m), 2.69(2H, t, J=7.9 Hz), 3.72(6H, d,J=11.0 Hz), 4.55(1H, br), 5.02(2H, s), 5.62(1H, dd, J=17.1, 18.3 Hz),6.75(1H, dd, J=17.1, 22.6 Hz), 6.80-6.89(1H, m), 6.93-6.96(2H, m),7.10(1H, d, J=7.9 Hz), 7.15(1H, dd, J=1.8, 7.9 Hz), 7.23(1H, t, J=7.9Hz), 7.31-7.41(6H, m).

Example 259 Dimethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-methylhexylphosphonate

The compound of Example 258 was reacted in the same manner as inReference Example 123 to obtain the desired product as a pale yellowoil.

FABMS: 648 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.13(3H, s), 1.41(9H, s), 1.50-1.60(2H, m),1.65-1.86(4H, m), 2.02-2.08(2H, m), 2.68(2H, t, J=7.3 Hz), 3.73(6H, d,J=11.0 Hz), 4.32(1H, br), 5.01(2H, s), 6.87(1H, dd, J=2.4, 8.5 Hz),6.91-6.95(2H, m), 7.11(1H, d, J=7.9 Hz), 7.14(1H, dd, J=1.8, 7.9 Hz),7.22(1H, t, J=7.9 Hz), 7.31-7.40(6H, m).

Example 2603-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-methylhexylphophonicacid

The compound of Example 259 was reacted in the same manner as inReference Example 236 to obtain the desired product as a colorlesspowder.

FABMS: 520 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.16(3H, s), 1.20(2H, br), 1.50-1.60(6H, m),1.73(2H, t, J=7.3 HZ), 2.65-2.70(2H, m), 5.07(2H, s), 6.89(1H, d, J=7.4Hz), 6.94-6.98(2H, m), 7.21-7.22(1H, m), 7.31-7.37(8H, m).

m.p.=195-197° C.

Example 2613-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-methyl-1-hexenylphosphonicacid

The compound of Example 258 was reacted in the same manner as in Example236 to obtain the desired product as a colorless powder.

FABMS: 518 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.25(3H, s), 1.39-1.57(2H, m), 1.65-1.79(2H,m), 2.52-2.70(2H, m), 5.05(2H, s), 5.77-5.94(1H, m), 6.08-6.26(1H, m),6.85(1H, d, J=6.7 Hz), 6.91-6.99(2H, m), 7.10-7.42(9H, m), 8.39-9.20(2H,br).

m.p.=243-245° C. Elemental analysis (%): C₂₆H₂₉ClFNO₄PS.H₂O C H N Calcd:58.26 5.83 2.61 Found: 57.80 5.31 2.74

Example 262 Dimethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-methoxymethyloxymethyl-1-hexenylphosphonate

The compound of Example 222 was reacted in the same manner as in Example232 to obtain the desired product as a colorless oil.

FABMS: 706 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.41(9H, s), 1.56-1.69(2H, m), 1.75-1.90(1H,m), 1.93-1.99(1H, m), 2.69(2H, t, J=7.9 Hz), 3.33(3H, s), 3.60-3.63(2H,m), 3.71(6H, d, J=11.0 Hz), 4.58(2H, s), 4.88(1H, br), 5.02(2H, s),5.70(1H, dd, J=17.7, 18.4 Hz), 6.75(1H, dd, J=17.7, 23.2 Hz), 6.87(1H,dd, J=2.4, 9.2 Hz), 6.92-6.96(2H, m), 7.10(1H, d, J=7.9), 7.14(1H, dd,J=1.8, 7.9 Hz), 7.23(1H, t, J=7.9 Hz), 7.30-7.41(6H, m).

Example 2633-amino-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethyl-1-hexenylphosphonicacid

The compound of Example 262 was reacted in the same manner as in Example236 to obtain the desired product as a colorless powder.

FABMS: 534 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.46-1.74(4H, m), 2.57-2.61(2H, m),3.47-3.52(2H, m), 5.07(2H, s), 5.87-5.96(1H, m), 6.03-6.16(1H, m),6.87(1H, d, J=7.3 Hz), 6.95-6.97(2H, m), 7.19(1H, d, J=9.0 Hz),7.27-7.39(8H, m), 7.81-8.83(2H, br).

m.p.=243-246° C.

Example 264 Dimethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-methoxymethyloxymethylhexylphosphonate

The compound of Example 262 was reacted in the same manner as inReference Example 123 to obtain the desired product as a colorlesspowder.

FABMS: 708 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.41(9H, s), 1.51-1.67(2H, m), 1.70-2.05(6H,m), 2.68 (2H, t, J=7.9 Hz), 3.33(3H, s), 3.47-3.53(2H, m), 3.73(6H, d,J=11.0 Hz), 4.58(2H, s), 4.61(1H, br), 5.02(2H, s), 6.88(1H, dd, J=1.8,7.9 Hz), 6.92-6.96(2H, m), 7.11(1H, d, J=7.9 Hz), 7.14(1H, dd, J=1.8,7.9 Hz), 7.23(1H, t, J=7.9 Hz), 7.30-7.41(6H, m).

Example 2653-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylhexylphosphonicacid

The compound of Example 264 was reacted in the same manner as in Example236 to obtain the desired product as a colorless powder.

FABMS: 536 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.36-1.73(8H, m), 2.60-2.68(2H, m),3.31-3.40(2H, m), 5.07(2H, s), 6.88(1H, d, J=7.9 Hz), 6.96-6.98(2H, m),7.20-7.40(9H, m), 7.94-8.94(2H, br).

m.p.=193-196° C. Elemental analysis (%): C₂₆H₃₁ClNO₅PS.1H₂O C H N Calcd:56.36 6.00 2.53 Found: 56.18 5.61 2.51

Example 266 Dimethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-methoxymethyloxymethyl-1-pentenylphosphonate

Following the same procedure as in Example 193, the compound of Example219 was oxidized and, following the same procedure as in Example 232,the product was reacted with methyl methylenebisphosphonate to obtainthe desired product as a colorless oil.

FABMS: 692 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.45(9H, s), 2.10-2.17(2H, m), 2.66-2.73(2H,m), 3.36(3H, s), 3.67-3.78(2H, m), 3.73(6H, d, J=11.0 Hz), 4.63(2H, s),4.80-4.85(1H, br), 5.02(2H, s), 5.78(1H, dd, J=17.8, 18.3 Hz), 6.82(1H,dd, J=17.8, 24.2 Hz), 6.87-6.95(3H, m), 7.12-7.13(2H, m), 7.23(1H, t,J=7.9 Hz), 7.30-7.41(6H, m).

Example 2673-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethyl-1-pentenylphosphonicacid

The compound of Example 266 was reacted in the same manner as in Example236 to obtain the desired product as a colorless powder.

FABMS: 520 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.76-1.98(2H, br), 2.50-2.72(2H, br),3.47-3.70(3H, m), 5.05(2H, s), 6.03-6.11(1H, m), 6.21-6.33(1H, m),6.85(1H, d, J=7.4 Hz), 6.94(2H, m), 7.15-7.36(9H, m), 8.74(2H, br s).

m.p.=245-248° C.

Example 268 Dimethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-methoxymethyloxymethylpentylphosphonate

The compound of Example 266 was reacted in the same manner as inReference Example 123 to obtain the desired product as a colorless oil.

FABMS: 694 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.44(9H, s), 1.54-1.60(2H, m), 1.82-1.87(2H,m), 1.98-2.05(2H, m), 2.67-2.70(2H, m), 3.39(3H, s), 3.58-3.64(2H, m),3.74(6H, d, J=11.0 Hz), 4.64(2H, s), 4.74(1H, br), 5.02(2H, s), 6.87(1H,dd, J=1.8, 7.9 Hz), 6.91-6.95(2H, m), 7.10-7.15(2H, m), 7.23(1H, t,J=7.9 Hz), 7.31-7.41(6H, m).

Example 2693-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylpentylphosphonicacid

The compound of Example 268 was reacted in the same manner as in Example236 to obtain the desired product as a colorless oil.

FABMS: 522 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.45-1.58(2H, m), 1.69-1.91(4H, m),2.58-2.72(2H,m), 3.10-3.75(2H, br), 5.07(2H, s), 6.88(1H, d, J=7.3 Hz),6.96-6.99(2H, m), 7.21(1H, d, J=7.9 Hz), 7.27-7.40(8H, m), 7.93-9.02(2H,br).

m.p.=205-208° C. Elemental analysis (%): C₂₅H₂₉ClNO₅PS.H₂O C H N Calcd:55.60 5.79 2.59 Found: 55.21 5.40 2.68

Example 270(+)-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylbutylphosphonatemonoester ((+)-Example 237)

Example 245 (250 mg) was dissolved in a 10% hydrochloric acid-methanolsolution (10 mL) and the mixture was allowed to stand overnight.Subsequently, the solvent was removed by distillation and the residuewas dissolved in ethyl acetate, followed by addition of triethylamine toadjust the pH to 7. The crystallized triethylamine hydrochloride wasseparated by filtration and was washed with ethyl acetate. The solventwas removed by distillation to give a Boc-free product as a colorlessoil (250 mg). This product was dissolved in acetonitrile (5 mL) whilethe solution was chilled in an ice bath. To this solution,trimethylsilyl iodide (26.7 μL) was added and the mixture was stirredfor 30 min at the same temperature. Subsequently, the solvent wasremoved by distillation and the residue was purified on a silica gelcolumn chromatography (reversed phase silica chromatography,water:acetonitrile=9:1 to 6:1 to 3:1 to 1:1 to only acetonitrile) togive the desired product as a colorless powder (97 mg).

[α]^(25° C.)=+2.77 (c=1.00, DMSO)

FABMS: 524 ([M+H]⁺).

¹H-NMR(400 MHz, DMSO+TFA) δ 1.78-1.85(2H, m), 2.78-2.80(2H, m), 3.56(1H,d, J=11.0 Hz), 3.61 (1H, d, J=11.0 Hz), 3.97(2H, d, J=5.5 Hz), 5.08(2H,s), 6.87-6.98(3H, m), 7.20-7.38(9H, m). Elemental analysis (%):C₂₄H₂₇ClNO₆PS.H₂O C H N Calcd: 53.56 5.25 2.60 Found: 53.21 5.25 2.41

Example 271(−)-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylbutylphosphonicacid monoester ((−)-Example 237)

Using the compound of Example 246, the reaction was carried out in thesame manner as in Example 270 to obtain the desired product as acolorless powder.

[α]^(25° C.)=−2.61 (c=1.00, DMSO).

FABMS: 524 ([M+H]⁺).

¹H-NMR(400 MHz, DMSO+TFA) δ 1.76-1.85(2H, m), 2.68-2.78(2H, m), 3.57(1H,d, J=11.0 Hz), 3.60 (1H, d, J=11.0 Hz), 3.97(2H, d, J=5.5 Hz), 5.08(2H,s), 6.87-6.98(3H, m), 7.20-7.38(9H, m).

Example 272 Ethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methoxycarbonylamino-2-propylpentanoate

Using diethyl propylmalonate, the compound of Reference Example 252 wasreacted in the same manner as in Example 194 to obtain ethyl5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethoxycarbonyl-2-propylpentanoateas a yellow oil. This product was hydrolyzed as in Example 198 to obtaina half ester. The half ester was treated in the same manner as inExample 202 to obtain the desired product as a colorless oil.

¹H-NMR(400 MHz, CDCl₃) δ 0.87(3H, t, J=7.3 Hz), 0.89-1.02(1H, m),1.24(3H, t, J=7.3 Hz), 1.23-1.33(2H, m), 1.52-1.78(3H, m), 2.24-2.40(2H,m), 2.63-2.68(2H, m), 3.62(3H, s), 4.17-4.22(2H, m), 5.02(2H, s),5.79(1H, br s), 6.85-6.94(3H, m), 7.09(1H, d, J=7.9 Hz), 7.14(1H, dd,J=1.8, 7.9 Hz), 7.22(1H, t, J=7.9 Hz), 7.29-7.43(6H, m).

Example 2735-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methoxycarbonylamino-2-propylpentane-1-ol

Using the compound of Example 272, the reaction was carried out in thesame manner as in Example 76 to obtain the desired product as acolorless oil.

FABMS: 528 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.90(3H, t, J=7.3 Hz), 1.15-1.35(2H, m),1.48-1.69(6H, m), 2.69(2H, t, J=7.3 Hz), 3.62(3H, s), 3.70(2H, s),4.71(1H, br s), 5.01(2H, s), 6.85-6.94(3H, m), 7.12-7.24(3H, m),7.31-7.40(6H, m).

Example 2745-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-propylpentane-1-ol

Using the compound of Example 273, the reaction was carried out in thesame manner as in Example 226 to synthesize2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-propylpentane-1-ol.As in Example 229, the product was reacted to form a Boc product,thereby obtaining the desired compound as a colorless oil.

¹H-NMR(400 MHz, CDCl₃) δ 0.90(3H, t, J=7.3 Hz), 1.15-1.35(2H, m),1.42(9H, s), 1.48-1.73(6H, m), 2.70(2H, t, J=7.3 Hz), 3.63-3.66(2H, m),4.51(1H, br s), 5.02(2H, s), 6.86-6.95(3H, m), 7.12-7.24(3H, m),7.33-7.41(6H, m).

Examples 275 and 276 (+) and(−)-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-propylpentane-1-ols

The compound of Example 274 was optically resolved by HPLC (chiralpakOD-H, hexane:ethanol=97:3, detection wavelength=UV 254 nm, flow rate=3mL/min). The desired products were obtained from the first eluate(Example 275) and the second eluate (Example 276), respectively, each asa colorless oil.

Example 275 [α]²⁵ _(D)−10.2° (C=1.08, CHCl₃);

Example 276 [α]²³ _(D)+9.48° (C=1.16, CHCl₃).

Example 2775-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-t-butoxycarbonylamino-2-propylpentanal

Using the compound of Example 274, the reaction was carried out in thesame manner as in Example 193 to obtain the desired product as acolorless oil.

¹H-NMR(400 MHz, CDCl₃) δ 0.88(3H, t, J=7.3 Hz), 1.03-1.37(2H, m),1.42(9H, s), 1.48-1.77(4H, m), 2.02-2.25(2H, m), 2.65-2.70(2H, m),5.02(2H, s), 5.27(1H, br s), 6.86-6.94(3H, m), 7.07-7.14(2H, m),7.23(1H, t, J=7.8 Hz), 7.30-7.41(6H, m), 9.23(1H, s).

Example 278 Dimethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-propyl-1-hexenylphosphonate

As in Example 232, the compound of Example 277 was reacted with methylmethylenebisphosphonate to obtain the desired product as a colorlessoil.

FABMS: 674 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.88(3H, t, J=7.3 Hz), 1.17-1.23(2H, m),1.40(9H, m), 1.51-1.87(6H, m), 2.68(2H, t, J=7.9 Hz), 3.69(3H, d, J=11.0Hz), 3.70(1H, d, J=11.0 Hz), 4.47(1H, br), 5.02(2H, s), 5.59(1H, t,J=17.7 Hz), 6.65(1H, dd, J=23.3, 17.1 Hz), 6.86-6.89(3H, m),7.09-7.15(2H, m), 7.23(1H, t, J=7.9 Hz), 7.31-7.41(6H, m).

Example 279 Dimethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-propylhexylphosphonate

Using the compound of Example 278, the reaction was carried out in thesame manner as in Reference Example 123 to obtain the desired product asa colorless oil.

FABMS: 676 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.88(3H, t, J=7.3 Hz), 1.15-1.28(2H, m),1.40(9H, m), 1.51-2.02(10H, m), 2.67(2H, t, J=7.9 Hz), 3.72(6H, d,J=11.0 Hz), 4.13(1H, br), 5.02(2H, s), 6.87-6.95(3H, m), 7.10-7.25(3H,m), 7.32-7.39(6H, m).

Example 280 Dimethyl3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-propyl-1-hexenylphosphonatehydrochloride

Using the compound of Example 278, the reaction was carried out in thesame manner as in Example 233 to obtain the desired product as acolorless oil.

FABMS: 574 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 0.85(3H, t, J=7.3 Hz), 1.15-1.28(2H, m),1.53-1.76(6H, m), 2.66(2H, t, J=7.9 Hz), 3.59(3H, d, J=11.0 Hz),3.62(3H, d, J=11.0 Hz), 5.08(2H, s), 6.00(1H, t, J=17.7 Hz), 6.57(1H,dd, J=23.8, 17.7 Hz), 6.89-7.00(3H, m), 7.22-7.41(9H, m), 8.47(3H, brs).

Examples 281 and 282 Dimethyl (+)- and(−)-3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-propyl-1-hexenylphosphonatehydrochlorides

Using the compound of Example 275, the same procedures as in Examples277, 278 and 280 were sequentially followed to obtain the desiredproduct as a pale yellow amorphous compound ([α]^(28.2) _(D)+2.9°(C=1.0, MeOH)) (Example 281). Furthermore, using the compound of Example276, the same procedure was followed as in Example 281 to obtain thedesired product as a pale yellow amorphous compound ([α]^(28.1)_(D)−1.9° (C=1.0, MeOH)) (Example 282).

Example 2833-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-propyl-1-hexenylphosphonicacid

Using the compound of Example 278, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 546 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 0.85(3H, t, J=7.3 Hz), 1.19-1.21(2H, m),1.51-1.69(6H, m), 2.67(2H, t, J=7.9 Hz), 5.08(2H, s), 5.87(1H, dd,J=17.7, 15.2 Hz), 6.32(1H, dd, J=23.8, 17.7 Hz), 6.88-7.00(3H, m),7.22-7.41(9H, m). Elemental analysis (%): C₂₈H₃₃ClNO₄PS.2/3H₂O C H NCalcd: 60.26 6.20 2.51 Found: 60.11 5.91 2.32

Example 2843-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-propylhexylphosphonicacid

Using the compound of Example 279, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 548 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 0.85(3H, t, J=7.3 Hz), 1.18-1.21(2H, m),1.42-1.54(8H, m), 1.68-1.74(2H, m), 2.67(2H, br s), 5.08(2H, s),6.88-7.00(3H, m), 7.22-7.41(9H, m). Elemental analysis (%):C₂₈H₃₅ClNO₄PS.H₂O C H N Calcd: 59.41 6.59 1.83 Found: 59.05 6.14 2.29m.p. = 197-199° C.

Example 2854-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-4-ethoxyphosphorylmethyl-2-oxazolidinone

The compound of Example 188 (330 mg) was dissolved in triethyl phosphite(120 μL) and the solution was refluxed for 3 hours. Subsequently, thereaction mixture was purified on a silica gel column chromatography(hexane:ethyl acetate=1:1 to 1:5) to give the desired product as a paleyellow oil (320 mg).

FABMS: 604 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.31-1.35(6H, m), 1.59-1.72(2H, m),1.84-1.88(2H, m), 2.10(1H, d, J=19.0 Hz), 2.11(1H, d, J=19.0 Hz),2.74(2H, t, J=7.3 Hz), 4.06-4.14(5H, m), 4.17-4.20(1H, m), 5.03(2H, s),5.89(1H, br s), 6.88(1H, dd, J=1.2, 7.3 Hz), 6.94-6.97(2H, m), 7.10(1H,d, J=7.9 Hz), 7.14(1H, dd, J=1.8, 7.9 Hz), 7.24(1H, t, J=7.9 Hz),7.31-7.41(6H, m).

Example 2862-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylpentylphosphonatehydrochloride

The compound of Example 285 was reacted in the same manner as in Example190 and the resulting compound was reacted in the same manner as inExample 233 to obtain the desired product as a colorless powder.

FABMS: 522 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.54-1.62(2H, m), 1.72-1.78(2H, m),2.64-2.66(2H, m), 3.20-3.31(2H, m), 3.43-3.52(2H, m), 5.08(2H, s),6.88-6.90(1H, m), 6.94-7.00(2H, m), 7.21-7.24(1H, dd, J=2.5, 7.9 Hz),7.29-7.41(8H, m).

m.p.=98-101° C. Elemental analysis (%): C₂₅H₂₉ClNO₅PS.HCl C H N Calcd:53.77 5.41 2.51 Found: 54.18 5.29 2.49

Example 287 Dimethyl7-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-t-butyldimethylsiloxymethyl-1-heptenylphosphonate

The compound of Example 130 was reacted with t-BuMe₂SiCl in the samemanner as in Example 191. The resulting silyl product was oxidized inthe same manner as in Example 193 to obtain an aldehyde. Subsequently,this aldehyde was reacted with methyl methylenebisphosphonate in thesame manner as in Example 232 to obtain the desired product as a paleyellow oil.

FABMS: 790 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.04(6H, s), 0.89(9H, s), 1.30-1.37(2H, m),1.41(9H, s), 1.50-1.60(2H, m), 1.75-1.85(2H, m), 2.68(2H, t, J=7.3 Hz),3.64-3.70(2H, m), 3.71(6H, d, J=11.6 Hz), 4.77(1H, br s), 5.02(2H, s),5.67(1H, dd, J=17.1, 18.3 Hz), 6.72(1H, dd, J=17.1, 22.6 Hz),6.67-6.88(1H, m), 6.91-6.94(2H, m), 7.11(1H, d, J=7.9 Hz), 7.14(1H, dd,J=1.8, 7.9 Hz), 7.22(1H, t, J=7.9 Hz), 7.31-7.39(6H, m).

Example 288 Dimethyl7-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-hydroxymethylheptylphosphonate

The compound of Example 287 was reduced in the same manner as inReference Example 123 and the resulting compound (107 mg) was dissolvedin tetrahydrofuran (5.0 mL). A 1 mol/L TBAF-tetrahydrofuran solution(160 μL) was added dropwise and the mixture was stirred for 3 hours atroom temperature. Subsequently, water was added and the reaction mixturewas extracted with ethyl acetate. The extract was washed sequentiallywith water and a saturated aqueous solution of sodium chloride and theorganic phase was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation and the residue was purified on a silica gelcolumn chromatography (ethyl acetate only) to obtain the desired productas a colorless oil (47 mg).

FABMS: 678 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.42(9H, s), 1.25-1.38(6H, s), 1.70-1.80(2H,m), 1.83-1.95(2H, m), 2.70(2H, t, J=7.9 Hz), 3.62(2H, br s), 3.75(6H, d,J=11.0 Hz), 4.63(1H, br s), 5.02(2H, s), 6.86-6.89(1H, m), 6.92-6.94(2H,m), 7.10-7.16(2H, m), 7.21-7.23(1H, m), 7.30-7.40(6H, m).

Example 2893-amino-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylheptylphosphonicacid

Using the compound of Example 288, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless powder.

FABMS: 550 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.22-1.32(2H, m), 1.48-1.60(6H, m),1.68-1.76(2H, m), 2.64-2.68(2H, m), 3.39-3.50(2H, m), 5.08(2H, s),6.88-6.90(1H, m), 6.95-6.99(2H, m), 7.20(1H, dd, J=1.9, 9.8 Hz),7.28-7.40(8H, m).

m.p.=180-183° C.

Example 2903-amino-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethyl-1-heptenylphosphonicacid

Following the same procedure as in Example 244, the compound of Example287 was desilylated and the resulting product was reacted in the samemanner as in Example 236 to obtain the desired product as a colorlesspowder.

FABMS: 548 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.27-1.38(2H, m), 1.43-1.52(2H, m),1.61-1.72(2H, m), 2.53-2.66(2H, m), 3.46-3.58(2H, m), 5.02(2H, s),5.88-5.97(1H, m), 6.06-6.17(1H, m), 6.85-6.87(1H, m), 6.94-6.96(2H, m),7.15-7.17(1H, m), 7.26-7.38(8H, m).

m.p.=258-260° C.

Example 291 Diethyl6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-t-butoxycarbonylamino-3-t-butyldimethylsilyloxy-1,1-difluoro-2-hydroxyhexylphosphonate

The compound of Example 128 was reacted with t-BuMe₂SiCl in the samemanner as in Example 191. The resulting silyl product was oxidized inthe same manner as in Example 193 to obtain an aldehyde. This aldehydewas reacted as follows: a 1.58 mol/L-LDA-tetrahydrofuran solution (1.50mL) was added to a tetrahydrofuran solution (9 mL) while the mixture waskept at −78° C. To the resulting mixture, diethyldifluoromethylphosphonate (372 μL) was added dropwise over 15 min andthe mixture was stirred for 20 min. To this mixture, the aldehyde (490mg) in tetrahydrofuran (1.0 mL) was added dropwise over 20 min while theinternal temperature was kept at −73° C. or below. Subsequently, themixture was stirred for 1.5 hours. A saturated aqueous solution ofammonium chloride was then added to the reaction mixture and the mixturewas extracted with ethyl acetate. The extract was washed sequentiallywith water and a saturated aqueous solution of sodium chloride and theorganic phase was dried over anhydrous sodium sulfate. The solvent wasremoved by distillation and the resulting residue was purified on asilica gel column chromatography (hexane:ethyl acetate=3:1) to obtainthe desired product as a colorless oil (439 mg).

FABMS: 858 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.06(6H, s), 0.88(9H, s), 1.33-1.40(6H, m),1.46(9H, s), 1.56-1.70(4H, m), 2.69(2H, t, J=7.3 Hz), 3.82-3.84(1H, m),4.23-4.33(6H, m), 5.02(2H, s), 5.05(1H, br s), 6.85-6.88(1H, m),6.91-6.95(2H, m), 7.12-7.14(2H, m), 7.22(1H, t, J=7.9 Hz), 7.31-7.40(6H,m).

Example 292 Diethyl3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-1,1-difluoro-2-hydroxy-3-hydroxymethylhexylphosphonatehydrochloride

Following the same procedure as in Example 244, the compound of Example291 was desilylated and the resulting product was reacted in the samemanner as in Example 233 to obtain the desired product as a colorlessamorphous product.

FABMS: 644 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.22-1.27(6H, m), 1.55-1.79(4H, m),2.62-2.65(2H, m), 3.59-3.73(2H, m), 4.04-4.11(4H, m), 4.68-4.90(1H, m),5.09(2H, s), 6.88-6.90(1H, m), 6.94-7.00(2H, m), 7.22-7.25(1H, m),7.29-7.41(8H, m).

Example 2933-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-1,1-difluoro-2-hydroxy-3-hydroxymethylhexylphosphonicacid

Using the compound of Example 292, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless amorphous product.

FABMS: 588 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.55-1.86(4H, m), 2.55-2.65(2H, m),3.51-3.67(4H, m), 3.78-3.84(1H, m), 5.08(2H, s), 6.88(1H, d, J=7.9 Hz),6.90-7.00(2H, m), 7.20-7.23(1H, m), 7.29-7.41(8H, m).

Example 294 Dimethyl3-t-butoxycarbonylamino-3-t-butyldimethylsiloxymethyl-6-[2-chloro-4-(3-trifluoromethylphenoxy)phenyl]hexylphosphonate

The compound of Example 149 was reacted with t-BuMe₂SiCl in the samemanner as in Example 191. The resulting silyl product was oxidized inthe same manner as in Example 193 to obtain an aldehyde. Subsequently,following the same procedure as in Example 232, this aldehyde wascondensed with methyl methylenebisphosphonate and, following the sameprocedure as in Reference Example 123, the resulting product was reducedto give the desired product as a colorless oil.

¹H-NMR(400 MHz, CDCl₃) δ 0.04(6H, s), 0.88(9H, s), 1.42(9H, s),1.56-1.64(4H, m), 1.64-1.77(2H, m), 1.90-1.97(2H, m), 2.69(2H, t, J=7.3Hz), 3.49-3.58(2H, m), 3.73(6H, d, J=11.0 Hz), 4.47(1H, br s), 6.85(1H,dd, J=2.5, 8.6 Hz), 7.01(1H, d, J=2.5 Hz), 7.14-7.18(2H, m),7.25-7.26(1H, m), 7.36(1H, t, J=7.9 Hz), 7.45(1H, t, J=7.9 Hz).

Example 295 Dimethyl3-amino-6-[2-chloro-4-(3-trifluoromethylphenoxy)phenyl]-3-hydroxymethylhexylphosphonatehydrochloride

Following the same procedure as in Example 244, the compound of Example294 was desilylated and the resulting product was reacted in the samemanner as in Example 233 to obtain the desired product as a colorlessamorphous product.

FABMS: 510 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.54-1.64(4H, m), 1.67-1.80(4H, m),2.65-2.69(2H, m), 3.40-3.41(2H, m), 3.68(6H, d, J=10.4 Hz), 5.51(1H, brs), 7.03(1H, dd, J=2.4, 8.6 Hz), 7.20(1H, d, J=2.4 Hz), 7.28-7.29(1H,m), 7.35(1H, s), 7.39(1H, d, J=7.9 Hz), 7.51(1H, d, J=7.9 Hz), 7.63(1H,t, J=7.9 Hz), 7.91(3H, br s).

Example 2963-amino-6-[2-chloro-4-(3-trifluoromethylphenoxy)phenyl]-3-hydroxymethylhexylphosphonicacid

Using the compound of Example 295, the reaction was carried out in thesame manner as in Example 236 to obtain the desired product as acolorless amorphous product.

FABMS: 482 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.48-1.60(6H, m), 1.60-1.75(2H, m),2.60-2.67(2H, m), 3.40(2H, s), 7.01(1H, dd, J=2.4, 7.9 Hz),7.15-7.19(1H, m), 7.28(1H, d, J=7.9 Hz), 7.35(1H, s), 7.39(1H, d, J=7.9Hz), 7.50(1H, d, J=7.9 Hz), 7.62(1H, t, J=7.9), 7.77-8.11(3H, br).

Example 297 Dimethyl3-amino-6-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]-3-hydroxymethylhexylphosphonatehydrochloride

The compound of Example 76 was reacted in the same manner as in Example294 and the resulting compound was reacted in the same manner as inExample 295 to obtain the desired product as a colorless oil.

FABMS: 525 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.46-1.62(4H, m), 1.62-1.83(4H, m),2.64-2.66(2H, m), 3.40-3.45(2H, m), 3.61(6H, d, J=10.4 Hz), 7.34(1H, dd,J=1.8, 8.0 Hz), 7.40-7.42(1H, m), 7.49(1H, dd, J=1.8 Hz), 7.54-7.56(1H,m), 7.59-7.62(2H, m), 7.66-7.68(1H, m), 7.86(3H, br s).

Example 2982-t-butoxycarbonylamino-2-t-butyldimethylsiloxymethyl-5-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]-1-dimethoxyphosphoryloxypentane

Following the same procedure as in Example 191, the compound of Example76 was reacted with t-BuMe₂SiCl and, following the same procedure as inExample 223, the resulting silyl product was reacted to give the desiredproduct as a colorless oil.

FABMS: 741 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 0.05(6H, s), 0.87(9H, s), 1.41(9H, s),1.60-1.91(4H, m), 2.71(2H, t, J=7.9 Hz), 3.60(1H, d, J=9.2 Hz), 3.64(1H,d, J=9.2 Hz), 3.76(6H, d, J=11.0 Hz), 4.09-4.15(2H, m), 4.66(1H, br),7.14-7.20(2H, m), 7.30-7.55(5H, m).

Example 2992-amino-5-[2-chloro-4-(3-trifluoromethylphenylthio)phenyl]-2-hydroxymethylpentylphosphonatemonoester

To a tetrahydrofuran solution (20 mL) of the compound of Example 298(1.29 g), a 1 mol/L TBAF-tetrahydrofuran solution (2.09 mL) was addeddropwise and the mixture was stirred for 4 hours at room temperature.Subsequently, water was added and the reaction mixture was extractedwith ethyl acetate. The extract was washed sequentially with water and asaturated aqueous solution of sodium chloride and the organic phase wasdried over anhydrous sodium sulfate. The solvent was removed bydistillation and the residue was purified on a silica gel columnchromatography (hexane:ethyl acetate=1:1 to ethyl acetate only) toobtain a desilylated product as a colorless oil (1.00 g). The resultingcompound (1.00 g) was dissolved in a 10% hydrochloric acid-methanolsolution (20 mL) and the mixture was left overnight at room temperature.Subsequently, the solvent was removed by distillation and the residuewas dissolved in ethyl acetate. The solution was neutralized withtriethylamine. The crystallized triethylamine hydrochloride wasseparated by filtration and the solvent was removed by distillation togive a colorless oil (1.00 g). The oil was dissolved in acetonitrile (15mL) while the solution was chilled in an ice bath. To this solution,TMSI (905 μL) was added and the mixture was stirred for 60 min. Thereaction mixture was concentrated and was purified on a silica gelcolumn chromatography (water:acetonitrile=9:1 to 6:1 to 3:1 to 1:1 toacetonitrile only) to obtain the desired product as a colorless powder(384 g).

FABMS: 500 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.60(4H, br s), 2.66(2H, br s), 3.36-3.45(2H,m), 3.68-3.76(2H, m), 7.32(1H, dd, J=1.8, 8.5 Hz), 7.38-7.45(2H, m),7.50-7.56(1H, m), 7.57-7.68(3H, m). Elemental analysis (%):C₁₉H₂₂ClF₅NO₅PS.1/4H₂O C H N Calcd: 45.24 4.50 2.78 Found: 45.05 4.312.72

Example 3002-amino-5-[2-chloro-4-(3-trifluoromethylphenoxy)phenyl]-2-hydroxymethylpentylphosphonatemonoester

The compound of Example 149 was reacted in the same manner as in Example298 and the resulting compound was reacted in the same manner as inExample 299 to obtain the desired product as a colorless powder.

FABMS: 484 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.61(4H, br), 2.64(2H, br), 3.41 (1H, d,J=11.6 Hz), 3.51(1H, d, J=11.6 Hz), 3.69-3.80(2H, m), 7.00(1H, dd,J=2.5, 8.6 Hz), 7.16(1H, d, J=2.5 Hz), 7.29(1H, dd, J=2.5, 8.6 Hz),7.35(1H, s), 7.40(1H, d, J=8.6 Hz), 7.50(1H, d, J=8.0 Hz), 7.61(1H, t,J=8.0 Hz).

Example 3012-amino-4-[2-chloro-4-(3-hydroxyphenylthio)phenyl]-2-hydroxymethylbutylphosphonatemonoester

Using the compound of Example 223, the reaction was carried out in thesame manner as in Example 238 to obtain the desired product as acolorless powder.

FABMS: 434 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.72-1.92(2H, m), 2.63-2.82(2H, m),3.48-3.60(2H, m), 3.71-3.90(2H, m), 6.66-6.78(3H, m), 7.14-7.37(4H, m).

Example 3022-t-butoxycarbonylamino-2-[2-chloro-4-(4-trifluoromethylphenoxy)phenyl]propyl-1,3-propanediol

The compound of Reference Example 323 was reacted in the same manner asin Example 1 and the resulting compound was reduced in the same manneras in Example 76 to obtain the desired product as a colorless powder.

¹H-NMR(400 MHz, CDCl₃) δ 1.44(9H, s), 1.57-1.74(4H, m), 2.70(2H, t,J=6.7 Hz), 3.33(2H, br s), 3.61(2H, d,d, J=6.7, 11.6 Hz), 3.84(2H, d,d,J=6.7, 11.6 Hz), 4.93(1H, br s), 6.89(1H, dd, J=2.5, 8.0 Hz),6.98-7.07(3H, m), 7.21(1H, d, J=8.6 Hz), 7.59(2H, d, J=8.6 Hz).

Example 3032-t-butoxycarbonylamino-2-[2-chloro-4-(2-trifluoromethylphenoxy)phenyl]propyl-1,3-propanediol

The compound of Reference Example 324 was reacted in the same manner asin Example 1 and the resulting compound was reduced in the same manneras in Example 76 to obtain the desired product as a colorless powder.

FABMS: 504 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.44(9H, s), 1.58-1.66(4H, m), 2.70(2H, t,J=6.7 Hz), 3.35(2H, br s), 3.60(2H, d,d, J=7.3, 11.6 Hz), 3.84(2H, d,d,J=7.3, 11.6 Hz), 4.92(1H, br s), 6.87(1H, dd, J=2.5, 8.0 Hz), 6.96(1H,d, J=8.0 Hz), 7.03(1H, d=2.5 Hz), 7.15-7.22(2H, m), 7.48(1H, t, J=7.3Hz), 7.68(1H, d, J=6.7 Hz).

Example 3042-t-butoxycarbonylamino-2-[4-(4-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol

The compound of Reference Example 327 was reacted in the same manner asin Example 1 and the resulting compound was reduced in the same manneras in Example 76 to obtain the desired product as a colorless oil.

FABMS: 543 ([M+H]⁺).

¹H-NMR(400 MHz, CDCl₃) δ 1.45(9H, s), 1.78-1.84(2H, m), 2.64-2.71(2H,m), 3.23-3.39(2H, m), 3.65(2H, d,d, J=6.7, 11.6 Hz), 3.84(2H, d,d,J=6.7, 11.6 Hz), 5.07(1H, s), 5.08(2H, s), 6.96-7.00(3H, m), 7.07-7.13(2H, m), 7.345-7.44(7H, m).

Example 305 Dimethyl3-amino-6-[2-chloro-4-(4-trifluoromethylphenoxy)phenyl]-3-hydroxymethylhexylphosphonatehydrochloride

The compound of Example 302 was treated in the same manner as in Example294 and the resulting compound was reacted in the same manner as inExample 295 to obtain the desired product as a colorless amorphousproduct.

FABMS: 510 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.51-1.60(4H, m), 1.65-1.82(4H, m), 2.68(2H,br s), 3.42(2H, s), 3.61(6H, d, J=11.0 Hz), 7.08(1H, dd, J=2.4, 8.6 Hz),7.15(2H, d, J=8.6 Hz), 7.26(1H, d, J=2.4 Hz), 7.42(1H, s, 8.6 Hz),7.75(2H, d, 8.6 HzHz), 7.89(3H, br s).

Example 306 Dimethyl3-amino-6-[2-chloro-4-(4-trifluoromethylphenoxy)phenyl]-3-hydroxymethyl-1-hexenylphosphonatehydrochloride

The compound of Example 303 was reacted in the same manner as in Example287 and the resulting compound was desilylated in the same manner as inExample 244. The desilylated product was then reacted in the same manneras in Example 233 to obtain the desired product as an amorphous product.

FABMS: 508 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.42-1.62(2H, m), 1.68-1.82(2H, m), 2.66(2H,t, J=2.7 Hz), 3.42 (2H, br s), 3.60(6H, d, J=11.0 Hz), 6.00(1H, t,J=17.7 Hz), 6.56(1H, dd, J=17.7, 22.6 Hz), 6.97(1H, dd, J=2.5, 8.6 Hz),7.11(1H, d, J=8.6 Hz), 7.13(1H, d=2.5 Hz), 7.32-7.40(2H, m), 7.67(1H, t,J=8.0 Hz), 7.79(1H, t, J=7.3 Hz), 8.22-8.38(3H, br s).

Example 307 Dimethyl3-amino-6-[2-chloro-4-(4-trifluoromethylphenoxy)phenyl]-3-hydroxymethylhexylphosphonatehydrochloride

Using the compound of Example 303, the reaction was carried out in thesame manner as in Example 305 to obtain the desired product as acolorless amorphous product.

FABMS: 510 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.50-1.60(4H, m), 1.65-1.82(4H, m),2.60-2.70(2H, m), 3.52-3.55(2H, m), 3.61(6H, d, J=11.0 Hz), 6.98(1H, dd,J=2.4, 8.6 Hz), 7.08(1H, d, J=8.6 Hz), 7.13(1H, d, J=2.4 Hz),7.33-7.41(2H, m), 7.68(1H, t, J=7.3), 7.80(1H, d, J=7.3 Hz),7.75-7.85(3H, br s).

Example 3083-amino-5-[4-(4-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylpentylphosphonicacid

The compound of Example 304 was reacted in the same manner as in Example294 and the resulting compound was reacted in the same manner as inExample 290 to obtain the desired product as a colorless powder.

FABMS: 522 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.47-1.62(2H, m), 1.62-1.91(4H, m),2.55-2.67(2H, m), 3.40-3.54(2H, m), 5.12(2H, s), 6.98-7.10(4H, m),7.25-7.51(8H, m).

Example 3092-amino-4-[4-(4-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylbutylphosphonatemonoester

The compound of Example 304 was reacted in the same manner as in Example298 and the resulting compound was reacted in the same manner as inExample 299 to obtain the desired product as a colorless powder.

FABMS: 524 ([M+H]⁺).

¹H-NMR(400 MHz, DMSOd₆) δ 1.70-1.77(2H, m), 2.65-2.69(2H, m),3.49-3.53(2H, m), 3.72-3.86(2H, m), 5.13(2H, s), 7.06-7.10(4H, m),7.25-7.27(1H, m), 7.33-7.46(7H, m).

Next, some experiment examples will be described, that demonstrate theefficacy of the compound of the present invention.

Experiment Example 1 Test for the Ability of Test Compounds to InduceIntracellular Ca²⁺ Mobilization in Cells Expressing Human S1P(sphingosine-1-phosphate) Receptors

CHO cells expressing human S1P receptors (i.e., CHO cells expressinghS1P₁ receptors or hS1P₃ receptors) were subcultured on Ham's F-12medium supplemented with 10% fetal bovine serum and 200 μg/mL Geneticin.The cells were seeded on a 96-well black clear bottom plate (COSTAR) at4×10⁴ cells/well and were cultured overnight at 37° C. in 5% CO₂. Afluorescent reagent that emits fluorescence upon binding to Ca²⁺(Calcium Screening Kit (DOJINDO)) was added to the culture and the cellswere further cultured for 60 min at 37° C. in 5% CO₂. After culturing,microplate spectrofluorometer (FLEX station, MOLECULAR DEVICE) was usedto measure the fluorescence intensity at an excitation wavelength of 485nm and a detection wavelength of 525 nm. S1P or a test compound adjustedwith cultural medium to a concentration 10 times higher than the finalconcentration (final DMSO concentration=0.1%). Each test compoundsolution was added 18 sec. after beginning of the measurement offluorescence. The fluorescence intensity was measured every 1.5 sec for100 sec. For each test compound, the difference between the maximumfluorescence intensity and the minimum fluorescence intensity (i.e.,increase in fluorescence) was determined from the measurements. The rateof fluorescence increase (%) for each test compound was calculated bythe difference (100%) of the fluorescence increase between solvent onlyand S1P (10⁻⁶M). Using this value as an index of the ability of the testcompound to induce intracellular Ca²⁺ mobilization, EC50 was determinedby PRISM software (GraphPad). In Table 11, the symbol “−” indicates thatthe test compound was determined to have an EC50 of 1 μmol/L or higher,the symbol “+” indicates that the test compound had an EC50 of lowerthan 1 μmol/L and higher than or equal to 0.1 μmol/L, the symbol “++”indicates that the test compound had an EC50 of lower than 0.1 μmol/Land higher than or equal to 0.01 μmol/L, and the symbol “+++” indicatesthat the test compound had an EC50 of lower than 0.01 μmol/L. TABLE 11Example No. S1P1 S1P3 236 ++ ++ 237 +++ +++ 238 + − 239 +++ +++ 240 ++ +241 + − 242 + − 249 ++ +++ 250 + − 253 + + 254 ++ − 260 ++ + 261 + − 263+++ + 265 +++ + 267 +++ − 269 ++ − 280 + + 283 ++ ++ 284 ++ + 286 ++ −290 +++ ++ 293 + + 296 ++ − 299 ++ − 300 ++ − 307 + − 308 + −

These results indicate that the compounds of the present invention acton human S1P receptors.

Experiment Example 2 Test for the Ability of Test Compounds to InduceActivation of Extracellular Regulatory Kinase (ERK) in Cells ExpressingHuman S1P Receptors

CHO cells expressing human S1P receptors (i.e., CHO cells expressinghS1P₄ receptors) were subcultured on Ham's F-12 medium supplemented with10% fetal bovine serum and 200 μg/mL Geneticin. The cells were seeded ona 6-well cell culture plate (COSTAR) at 3×10⁵ cells/well and werecultured overnight at 37° C. in 5% CO₂. On the following day, the mediumwas replaced with FBS-free Ham's F-12 medium (containing 0.1% fattyacid-free bovine serum albumin) and the cells were cultured overnight at37° C. in 5% CO₂. S1P or a test compound adjusted with Ham's F-12 medium(with 0.1% fatty acid-free bovine serum albumin) to a concentration 10times higher than the final concentration (final DMSOconcentration=0.1%). Each test compound solution was added to thisculture plate. The cells were cultured for 5 min at 37° C. in 5% CO₂.The medium was removed and the cells were washed with a 200 μmol/Lice-cold PBS containing Na₃VO₄. A lysis buffer (20 mmol/L Tris-HClpH7.5, 1% Triton X-100, 1 mmol/L EDTA, 1 mmol/L EGTA, 0.5 mmol/L Na₃VO₄,0.1% β-mercaptoethanol, 50 mmol/L NaF, 5 mmol/L Na₄O₇P₃, 10 mmol/LC₃H₇O₆Na, 1 μmol/L Microcystin LR, 1× complete Protease InhibitorCocktail (ROCHE)) was then added to the cells and the reaction wascarried out on ice for 5 min to lyse the cells. The cell lysate wassubjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis(SDS-PAGE) to separate proteins. The proteins were transferred to a PVDFmembrane (Hybond-P, Amersham Biosciences). The membrane was reactedovernight at 4° C. with anti-phospho ERK (p42/44 MAPK) monoclonalantibody (E10, Cell Signaling Technologies) diluted 1000-fold, and wassubsequently reacted for 1 hour at room temperature with alkalinephosphatase-labeled anti-mouse IgG antibody (Molecular Probe) diluted6000-fold. After washing with 20 mmol/L Tris-HCl and 150 mmol/L NaClsolution, the PVDF membrane was fluorostained with DDAO phosphate(DyeChrome Western Blot Stain Kit, Molecular Probe), a fluorescentsubstrate of alkaline phosphatase. The fluorescence was detected using avariable image analyzer (Typhoon 8600, Amersham Biosciences). Thedetected signal of phosphorylated ERK was quantified using ImageQuantsoftware (Molecular Dynamics). The rate of ERK activation (%) for eachtest compound was calculated by the difference (100%) of the signalintensity between solvent only and S1P (10⁻⁶ mol/L). The results areshown in Table 12 below. TABLE 12 Induction effect of ERK activation onCompound hS1P-expressing CHO cells (Activation Conc. rate (%) relativeto the activated ERK Example No. (nmol/L) at S1P10-6 mol/L) 236 1 8.0 10119.5 237 1 35.8 10 80.7

These results indicate that the compounds of the present inventioninduce ERK activation by acting on human S1P receptors.

Experiment Example 3

Inhibitory effects of test compounds on host vs. graft rejection in mice

This experiment was performed according to the method described inTransplantation 55(3) (1993): 578-591. Spleens were collected from 6 to16 week old male BALB/c mice (CHARLES RIVER JAPAN). The spleens wereplaced in an RPMI-1640 medium (SIGMA) and were gently pressed betweentwo slide glasses and then passed through a cell strainer (70 μm,Falcon) to form a cell suspension. The suspension was then centrifugedand the supernatant was discarded. An ammonium chloride-Tris isotonicbuffer was added to the suspension to lyse erythrocytes. The cells werethen centrifuged three times in RPMI-1640 medium for washing and wereresuspended in an RPMI-1640 medium. To this suspension, mitomycin C(KYOWA HAKKO KOGYO Co., Ltd.) was added to a final concentration of 25μg/mL and the suspension was incubated for 30 minutes at 37° C. in a 5%CO₂ atmosphere. The cells were centrifuged three times in RPMI-1640medium for washing and were resuspended in an RPMI-1640 medium so thatthe medium would contain 2.5×10⁸ cells/mL. This suspension served as a“stimulation cell suspension.” Using a 27G needle with a microsyringe(Hamilton), 20 μL (5×10⁶ cells/mouse) of the stimulation cell suspensionwas subcutaneously injected into the right hind footpad of 6 to 8 weekold male C3H/HeN mice (CLEA JAPAN). Normal control group was injectedwith RPMI-1640 medium alone. 4 days after the injection, right popliteallymph nodes were collected and were weighed on a Mettler AT201electronic scale (METTLER TOLEDO Co., Ltd.). Each animal wasintraperitoneally administered a test compound once a day for fourconsecutive days starting on the day of the injection of the stimulationcells (i.e., total of 4 times). Control groups were administered thesame vehicle as that used in the preparation of each test compound. Theresults are shown in Table 13 below. The inhibition (%) was determinedusing the following formula{[Weight of right popliteal lymph nodes of positive controlgroup]−[Weight of right popliteal lymph nodes of test compoundgroup]×100}/{[Weight of right popliteal lymph nodes of positive controlgroup]−[Weight of right popliteal lymph nodes of normal controlgroup]}  Formula 1

TABLE 13 Example Dose Inhibition No. (mg/kg) (%) 233 30 53 235 30 56 2360.03 73 237 0.1 75 238 3 65 239 0.03 65 241 10 46 242 10 62 247 0.03 63

INDUSTRIAL APPLICABILITY

As set forth, the present invention has been devised in recognition ofthe fact that the novel aminophosphonic acid derivatives with adiarylsulfide or diarylether group exhibit a strong ability to modulateS1P receptors. Effective modulators of S1P receptors, the compounds ofthe present invention have a great potential as a prophylactic ortherapeutic agent against peripheral vascular diseases, such asarteriosclerosis, arteriosclerosis obliterans, renal fibrosis, hepaticfibrosis, chronic bronchial asthma, diffuse pulmonaryhamartoangiomyomatosis, adult respiratory distress syndrome (ARDS),chronic obstructive pulmonary disease (COPD), interstitial pneumonia,idiopathic interstitial pneumonia, lung cancer, hypersensitivitypneumonitis, Buerger's disease, diabetic neuropathy, septicemia,angiitis, nephritis, pneumonia, cerebral infarction, myocardialinfarction, edema, varicose veins, dissecting arterial aneurysm,stenocardia, DIC, pleuritis, congestive heart failure, multiple organfailure, bed sore, burn, ulcerative colitis and Crohn's disease. Thecompounds of the present invention also act as effective prophylactic ortherapeutic agents against rejection of heart transplants, kidneytransplants, skin grafts, liver transplants and bone marrow transplants,or against rheumatoid arthritis, lupus nephritis, systemic lupuserythematosus, Hashimoto's disease, multiple sclerosis, myastheniagravis, diabetes, atopic dermatitis, allergic rhinitis, allergicconjunctivitis, allergic contact dermatitis and various other diseases.

1. An aminophosphonic acid derivative represented by the followinggeneral formula (1):

[wherein R₁ is a hydrogen atom, a halogen atom, a halogenated orunhalogenated lower alkyl group having 1 to 4 carbon atoms, a hydroxygroup, a phenyl group, an aralkyl group, a lower alkoxy group having 1to 4 carbon atoms, a trifluoromethyloxy group, a substituted orunsubstituted phenoxy group, a cyclohexylmethyloxy group, a substitutedor unsubstituted aralkyloxy group, a pyridylmethyloxy group, acinnamyloxy group, a naphthylmethyloxy group, a phenoxymethyl group, ahydroxymethyl group, a hydroxyethyl group, a lower alkylthio grouphaving 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, abenzylthio group, an acetyl group, a nitro group or a cyano group; R₂ isa hydrogen atom, a halogen atom, a halogenated or unhalogenated loweralkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to4 carbon atoms, an aralkyl group or an aralkyloxy group; R₃ is ahydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkylgroup having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4carbon atoms, a hydroxy group, a benzyloxy group, a phenyl group, alower alkoxymethyl group having 1 to 4 carbon atoms or a lower alkylthiogroup having 1 to 4 carbon atoms; R₄ is a hydrogen atom, a halogen atom,a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxymethylgroup having 1 to 4 carbon atoms, a lower alkylthiomethyl group having 1to 4 carbon atoms, a hydroxymethyl group, a phenyl group or an aralkylgroup; R₅ is a hydrogen atom or a lower alkyl group having 1 to 4 carbonatoms; X is O, S, SO or SO₂; Y is —CH₂O—, —CH₂—, —CH═CH—, —CH═CF—,—CH₂CH₂—, —CH₂CFH—, —CH₂CF₂— or —CH(OH)CF₂—; and n is an integer from 1to 4], and an optical isomer, and a pharmaceutically acceptable salt anda hydrate thereof.
 2. The 2-aminophosphonic acid monoester derivativeaccording to claim 1, and the optical isomer, and the pharmaceuticallyacceptable salt and the hydrate thereof, wherein the compoundsrepresented by the general formula (1) comprise compounds represented bythe following general formula (1a):

[wherein X, R₃, R₄ and n are as defined above].
 3. The 2-aminophosphonicacid monoester derivative according to claim 2, and the optical isomer,and the pharmaceutically acceptable salt and the hydrate thereof,wherein R₃ is a chlorine atom.
 4. The 3-aminophosphonic acid derivativeaccording to claim 1, and the optical isomer, and the pharmaceuticallyacceptable salt and the hydrate thereof, wherein the compoundrepresented by the general formula (1) comprise compounds represented bythe following general formula (1b):

[wherein Z is —CH₂—, —CH═CH—, —CH═CF—, —CH₂CH₂—, —CH₂CHF—, —CH₂CF₂— or—CH(OH)CF₂—; and X, R₃, R₄ and n are as defined above].
 5. The3-aminophosphonic acid derivative according to claim 4, and the opticalisomer, and the pharmaceutically acceptable salt and the hydratethereof, wherein R₃ is a chlorine atom.
 6. The aminophosphonic acidester derivative according to claim 1, and the pharmaceuticallyacceptable salt and the hydrate thereof, wherein the compoundrepresented by the general formula (1) is 1)2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylpentylphosphonicacid monoester, 2)2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutylphosphonicacid monoester, 3)2-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylpentylphosphonicacid monoester, 4)2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-hydroxymethylbutylphosphonicacid monoester, 5)3-amino-5-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylpentylphosphonicacid, or 6)3-amino-6-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-3-hydroxymethylhexylphosphonicacid,
 7. An S1P receptor modulator containing as an active ingredient atleast one of aminophosphonic acid derivatives represented by thefollowing general formula (1):

[wherein R₁ is a hydrogen atom, a halogen atom, a halogenated orunhalogenated lower alkyl group having 1 to 4 carbon atoms, a hydroxygroup, a phenyl group, an aralkyl group, a lower alkoxy group having 1to 4 carbon atoms, a trifluoromethyloxy group, a substituted orunsubstituted phenoxy group, a cyclohexylmethyloxy group, a substitutedor unsubstituted aralkyloxy group, a pyridylmethyloxy group, acinnamyloxy group, a naphthylmethyloxy group, a phenoxymethyl group, ahydroxymethyl group, a hydroxyethyl group, a lower alkylthio grouphaving 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, abenzylthio group, an acetyl group, a nitro group or a cyano group; R₂ isa hydrogen atom, a halogen atom, a halogenated or unhalogenated loweralkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to4 carbon atoms, an aralkyl group or an aralkyloxy group; R₃ is ahydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkylgroup having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4carbon atoms, a hydroxy group, a benzyloxy group, a phenyl group, alower alkoxymethyl group having 1 to 4 carbon atoms or a lower alkylthiogroup having 1 to 4 carbon atoms; R₄ is a hydrogen atom, a halogen atom,a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxymethylgroup having 1 to 4 carbon atoms, a lower alkylthiomethyl group having 1to 4 carbon atoms, a hydroxymethyl group, a phenyl group or an aralkylgroup; R₅ is a hydrogen atom or a lower alkyl group having 1 to 4 carbonatoms; X is O, S, SO or SO₂; Y is —CH₂O—, —CH₂—, —CH═CH—, —CH═CF—,—CH₂CH₂—, —CH₂CFH—, —CH₂CF₂— or —CH(OH)CF₂—; and n is an integer from 1to 4], and optical isomers, and pharmaceutically acceptable salts andhydrates thereof.
 8. The S1P receptor modulator according to claim 7,wherein the compound represented by the general formula (1) contains asan active ingredient at least one of 2-aminophosphonic acid monoesterderivatives represented by the following general formula (1a):

[wherein R₃, R₄, X and n are as defined above], and the optical isomers,the pharmaceutically acceptable salts and the hydrates thereof.
 9. TheS1P receptor modulator according to claim 7, wherein the compoundrepresented by the general formula (1) contains as an active ingredientat least one of 2-aminophosphonic acid derivatives represented by thefollowing general formula (1b):

[wherein R₃, R₄, X, Z and n are as defined above], and the opticalisomers, the pharmaceutically acceptable salts and the hydrates thereof.10. A pharmaceutical agent containing as an active ingredient at leastone of the aminophosphonic acid derivatives according to claim 1, andthe optical isomers, the pharmaceutically acceptable salts and thehydrates thereof.
 11. A pharmaceutical agent containing as an activeingredient at least one of the aminophosphonic acid derivativesaccording to claim 2, and the optical isomers, the pharmaceuticallyacceptable salts and the hydrates thereof.
 12. A pharmaceutical agentcontaining as an active ingredient at least one of the aminophosphonicacid derivatives according to claim 3, and the optical isomers, thepharmaceutically acceptable salts and the hydrates thereof.
 13. Apharmaceutical agent containing as an active ingredient at least one ofthe aminophosphonic acid derivatives according to claim 4, and theoptical isomers, the pharmaceutically acceptable salts and the hydratesthereof.
 14. A pharmaceutical agent containing as an active ingredientat least one of the aminophosphonic acid derivatives according to claim5, and the optical isomers, the pharmaceutically acceptable salts andthe hydrates thereof.
 15. A pharmaceutical agent containing as an activeingredient at least one of the aminophosphonic acid derivativesaccording to claim 6, and the optical isomers, the pharmaceuticallyacceptable salts and the hydrates thereof.
 16. A pharmaceutical agentcontaining as an active ingredient at least one of the aminophosphonicacid derivatives according to claim 7, and the optical isomers, thepharmaceutically acceptable salts and the hydrates thereof.
 17. Apharmaceutical agent containing as an active ingredient at least one ofthe aminophosphonic acid derivatives according to claim 8, and theoptical isomers, the pharmaceutically acceptable salts and the hydratesthereof.
 18. A pharmaceutical agent containing as an active ingredientat least one of the aminophosphonic acid derivatives according to claim9, and the optical isomers, the pharmaceutically acceptable salts andthe hydrates thereof.